Protease inhibitors

ABSTRACT

The present invention provides C 1-6 alkyl-4-amino-azepan-3-one protease inhibitors and pharmaceutically acceptable salts, hydrates and solvates thereof which inhibit proteases, including cathepsin K, pharmaceutical compositions of such compounds, novel intermediates of such compounds, and methods for treating diseases of excessive bone loss or cartilage or matrix degradation, including osteoporosis; gingival disease including gingivitis and periodontitis; arthritis, more specifically, osteoarthritis and rheumatoid arthritis; Paget&#39;s disease; hypercalcemia of malignancy; and metabolic bone disease; and parasitic diseases, including malaria, by administering to a patient in need thereof one or more compounds of the present invention.

CROSS REFERENCE TO PRIOR APPLICATIONS

This application is a continuation of Ser. No. 10/239,343 filed 20 Sep.2002 now U.S. Pat. No. 7,071,184, which is a 371 application ofPCT/US01/07094 filed 7 Mar. 2001, which claims the benefit of U.S.application 60/191,000 filed 21 Mar. 2000, U.S. application 60/206,341filed 23 May 2000, U.S. application 60/211,759 filed 14 Jun. 2000, andU.S. application 60/217,445 filed 10 Jul. 2000.

FIELD OF THE INVENTION

This invention relates in general to C₁₋₆alkyl-4-amino-azepan-3-oneprotease inhibitors, particularly such inhibitors of cysteine and serineproteases, more particularly compounds which inhibit cysteine proteases,even more particularly compounds which inhibit cysteine proteases of thepapain superfamily, yet more particularly compounds which inhibitcysteine proteases of the cathepsin family, most particularly compoundswhich inhibit cathepsin K. Such compounds are particularly useful fortreating diseases in which cysteine proteases are implicated, especiallydiseases of excessive bone or cartilage loss, e.g., osteoporosis,periodontitis, and arthritis; and certain parasitic diseases, e.g.,malaria.

BACKGROUND OF THE INVENTION

Cathepsins are a family of enzymes which are part of the papainsuperfamily of cysteine proteases. Cathepsins B, H, L, N and S have beendescribed in the literature. Recently, cathepsin K polypeptide and thecDNA encoding such polypeptide were disclosed in U.S. Pat. No. 5,501,969(called cathepsin O therein). Cathepsin K has been recently expressed,purified, and characterized. Bossard, M. J., et al., (1996) J. Biol.Chem. 271, 12517-12524; Drake, F. H., et al., (1996) J. Biol. Chem. 271,12511-12516; Bromme, D., et al., (1996) J. Biol. Chem. 271, 2126-2132.

Cathepsin K has also been variously denoted as cathepsin O or cathepsinO2 in the literature. The designation cathepsin K is considered to bethe most appropriate one.

Cathepsins function in the normal physiological process of proteindegradation in animals, including humans, e.g., in the degradation ofconnective tissue. However, elevated levels of these enzymes in the bodycan result in pathological conditions leading to disease. Thus,cathepsins have been implicated as causative agents in various diseasestates, including but not limited to, infections by pneumocystiscarinii, trypsanoma cruzi, trypsanoma brucei brucei, and Crithidiafusiculata; as well as in schistosomiasis, malaria, tumor metastasis,metachromatic leukodystrophy, muscular dystrophy, amytrophy, and thelike. See International Publication Number WO 94/04172, published onMar. 3, 1994, and references cited therein. See also European PatentApplication EP 0 603 873 A1, and references cited therein. Two bacterialcysteine proteases from P. gingivallis, called gingipains, have beenimplicated in the pathogenesis of gingivitis. Potempa, J., et al. (1994)Perspectives in Drug Discovery and Design, 2, 445-458.

Cathepsin K is believed to play a causative role in diseases ofexcessive bone or cartilage loss. Bone is composed of a protein matrixin which spindle- or plate-shaped crystals of hydroxyapatite areincorporated. Type I collagen represents the major structural protein ofbone comprising approximately 90% of the protein matrix. The remaining10% of matrix is composed of a number of non-collagenous proteins,including osteocalcin, proteoglycans, osteopontin, osteonectin,thrombospondin, fibronectin, and bone sialoprotein. Skeletal boneundergoes remodelling at discrete foci throughout life. These foci, orremodelling units, undergo a cycle consisting of a bone resorption phasefollowed by a phase of bone replacement.

Bone resorption is carried out by osteoclasts, which are multinuclearcells of hematopoietic lineage. The osteoclasts adhere to the bonesurface and form a tight sealing zone, followed by extensive membraneruffling on their apical (i.e., resorbing) surface. This creates anenclosed extracellular compartment on the bone surface that is acidifiedby proton pumps in the ruffled membrane, and into which the osteoclastsecretes proteolytic enzymes. The low pH of the compartment dissolveshydroxyapatite crystals at the bone surface, while the proteolyticenzymes digest the protein matrix. In this way, a resorption lacuna, orpit, is formed. At the end of this phase of the cycle, osteoblasts laydown a new protein matrix that is subsequently mineralized. In severaldisease states, such as osteoporosis and Paget's disease, the normalbalance between bone resorption and formation is disrupted, and there isa net loss of bone at each cycle. Ultimately, this leads to weakening ofthe bone and may result in increased fracture risk with minimal trauma.

Several published studies have demonstrated that inhibitors of cysteineproteases are effective at inhibiting osteoclast-mediated boneresorption, and indicate an essential role for a cysteine proteases inbone resorption. For example, Delaisse, et al., Biochem. J., 1980, 192,365, disclose a series of protease inhibitors in a mouse bone organculture system and suggest that inhibitors of cysteine proteases (e.g.,leupeptin, Z-Phe-Ala-CHN₂) prevent bone resorption, while serineprotease inhibitors were ineffective. Delaisse, et al., Biochem.Biophys. Res. Commun., 1984, 125, 441, disclose that E-64 and leupeptinare also effective at preventing bone resorption in vivo, as measured byacute changes in serum calcium in rats on calcium deficient diets.Lerner, et al., J. Bone Min. Res., 1992, 7, 433, disclose that cystatin,an endogenous cysteine protease inhibitor, inhibits PTH stimulated boneresorption in mouse calvariae. Other studies, such as by Delaisse, etal., Bone, 1987, 8, 305, Hill, et al., J. Cell. Biochem., 1994, 56, 118,and Everts, et al., J. Cell. Physiol., 1992, 150, 221, also report acorrelation between inhibition of cysteine protease activity and boneresorption. Tezuka, et al., J. Biol. Chem., 1994, 269, 1106, Inaoka, etal., Biochem. Biophys. Res. Commun., 1995, 206, 89 and Shi, et al., FEBSLett., 1995, 357, 129 disclose that under normal conditions cathepsin K,a cysteine protease, is abundantly expressed in osteoclasts and may bethe major cysteine protease present in these cells.

The abundant selective expression of cathepsin K in osteoclasts stronglysuggests that this enzyme is essential for bone resorption. Thus,selective inhibition of cathepsin K may provide an effective treatmentfor diseases of excessive bone loss, including, but not limited to,osteoporosis, gingival diseases such as gingivitis and periodontitis,Paget's disease, hypercalcemia of malignancy, and metabolic bonedisease. Cathepsin K levels have also been demonstrated to be elevatedin chondroclasts of osteoarthritic synovium. Thus, selective inhibitionof cathepsin K may also be useful for treating diseases of excessivecartilage or matrix degradation, including, but not limited to,osteoarthritis and rheumatoid arthritis. Metastatic neoplastic cellsalso typically express high levels of proteolytic enzymes that degradethe surrounding matrix. Thus, selective inhibition of cathepsin K mayalso be useful for treating certain neoplastic diseases.

Several cysteine protease inhibitors are known. Palmer, (1995) J. Med.Chem., 38, 3193, disclose certain vinyl sulfones which irreversiblyinhibit cysteine proteases, such as the cathepsins B, L, S, O2 andcruzain. Other classes of compounds, such as aldehydes, nitriles,α-ketocarbonyl compounds, halomethyl ketones, diazomethyl ketones,(acyloxy)methyl ketones, ketomethylsulfonium salts and epoxy succinylcompounds have also been reported to inhibit cysteine proteases. SeePalmer, id, and references cited therein.

U.S. Pat. No. 4,518,528 discloses peptidyl fluoromethyl ketones asirreversible inhibitors of cysteine protease. Published InternationalPatent Application No. WO 94/04172, and European Patent Application Nos.EP 0 525 420 A1, EP 0 603 873 A1, and EP 0 611 756 A2 describealkoxymethyl and mercaptomethyl ketones which inhibit the cysteineproteases cathepsins B, H and L. International Patent Application No.PCT/US94/08868 and and European Patent Application No. EP 0 623 592 A1describe alkoxymethyl and mercaptomethyl ketones which inhibit thecysteine protease IL-1βconvertase. Alkoxymethyl and mercaptomethylketones have also been described as inhibitors of the serine proteasekininogenase (International Patent Application No. PCT/GB91/01479).

Azapeptides which are designed to deliver the azamino acid to the activesite of serine proteases, and which possess a good leaving group, aredisclosed by Elmore et al., Biochem. J., 1968, 107, 103, Garker et al.,Biochem. J., 1974, 139, 555, Gray et al., Tetrahedron, 1977, 33, 837,Gupton et al., J. Biol. Chem., 1984, 259, 4279, Powers et al., J. Biol.Chem., 1984, 259, 4288, and are known to inhibit serine proteases. Inaddition, J. Med. Chem., 1992, 35, 4279, discloses certain azapeptideesters as cysteine protease inhibitors.

Antipain and leupeptin are described as reversible inhibitors ofcysteine protease in McConnell et al., J. Med. Chem., 33, 86; and alsohave been disclosed as inhibitors of serine protease in Umezawa et al.,45 Meth. Enzymol. 678. E64 and its synthetic analogs are also well-knowncysteine protease inhibitors (Barrett, Biochem. J., 201, 189, andGrinde, Biochem. Biophys. Acta, 701, 328).

1,3-diamido-propanones have been described as analgesic agents in U.S.Pat. Nos. 4,749,792 and 4,638,010.

Thus, a structurally diverse variety of protease inhibitors have beenidentified. However, these known inhibitors are not considered suitablefor use as therapeutic agents in animals, especially humans, becausethey suffer from various shortcomings. These shortcomings include lackof selectivity, cytotoxicity, poor solubility, and overly rapid plasmaclearance. A need therefore exists for methods of treating diseasescaused by pathological levels of proteases, particularly cysteineproteases, more particularly cathepsins, most particularly cathepsin K,and for novel inhibitor compounds useful in such methods.

We have now discovered a novel class of C₁₋₆alkyl-4-amino-azepan-3-onecompounds which are protease inhibitors, most particularly of cathepsinK.

SUMMARY OF THE INVENTION

An object of the present invention is to provideC₁₋₆alkyl-4-amino-azepan-3-one carbonyl protease inhibitors,particularly such inhibitors of cysteine and serine proteases, moreparticularly such compounds which inhibit cysteine proteases, even moreparticularly such compounds which inhibit cysteine proteases of thepapain superfamily, yet more particularly such compounds which inhibitcysteine proteases of the cathepsin family, most particularly suchcompounds which inhibit cathepsin K, and which are useful for treatingdiseases which may be therapeutically modified by altering the activityof such proteases.

Accordingly, in the first aspect, this invention provides a compoundaccording to Formula I.

In another aspect, this invention provides a pharmaceutical compositioncomprising a compound according to Formula I and a pharmaceuticallyacceptable carrier, diluent or excipient.

In yet another aspect, this invention provides intermediates useful inthe preparation of the compounds of Formula I.

In still another aspect, this invention provides a method of treatingdiseases in which the disease pathology may be therapeutically modifiedby inhibiting proteases, particularly cysteine and serine proteases,more particularly cysteine proteases, even more particularly cysteineproteases of the papain superfamily, yet more particularly cysteineproteases of the cathepsin family, most particularly cathepsin K.

In a particular aspect, the compounds of this invention are especiallyuseful for treating diseases characterized by bone loss, such asosteoporosis and gingival diseases, such as gingivitis andperiodontitis, or by excessive cartilage or matrix degradation, such asosteoarthritis and rheumatoid arthritis; and for treating certainparasitic diseases, such as malaria.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds of Formula I:

wherein:

R¹ is selected from the group consisting of:

R² is selected from the group consisting of: H, C₁₋₆alkyl,C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar—C₀₋₆alkyl, Het-C₀₋₆alkyl, R⁹C(O)—, R⁹C(S)—,R⁹SO₂—, R⁹OC(O)—, R⁹R¹¹NC(O)—, R⁹R¹¹NC(S)—, R⁹(R¹¹)NSO₂—

R³ is selected from the group consisting of: H, C₁₋₆alkyl,C₃₋₆cycloalkyl-C₀₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, HetC₀₋₆alkyl,ArC₀₋₆alkyl, Ar—ArC₀₋₆alkyl, Ar—HetC₀₋₆alkyl, Het-ArC₀₋₆alkyl, andHet-HetC₀₋₆alkyl;

R³ and R′ may be connected to form a pyrrolidine, piperidine ormorpholine ring;

R⁴ is selected from the group consisting of: H, C₁₋₆alkyl,C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar—C₀₋₆alkyl, Het-C₀₋₆alkyl, R⁵C(O)—, R⁵C(S)—,R⁵SO₂—, R⁵OC(O)—, R⁵R¹²NC(O)—, and R⁵R¹²NC(S)—;

R⁵ is selected from the group consisting of: H, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₆cycloalkyl-C₀₋₆alkyl, C₂₋₆alkanonyl, Ar—C₀₋₆alkyl andHet-C₀₋₆alkyl;

R⁶ is selected from the group consisting of: H, C₁₋₆alkyl, Ar—C₀₋₆alkyl,and Het-C₀₋₆alkyl;

R⁷ is selected from the group consisting of: H, C₁₋₆alkyl,C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar—C₀₋₆alkyl, Het-C₀₋₆alkyl, R¹⁰C(O)—,R¹⁰C(S)—, R¹⁰SO₂—, R¹⁰OC(O)—, R¹⁰R¹³NC(O)—, and R¹⁰R¹³NC(S)—;

R⁸ is selected from the group consisting of: H, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, HetC₀₋₆alkyl and ArC₀₋₆alkyl;

R⁹ is selected from the group consisting of: C₁₋₆alkyl,C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar—C₀₋₆alkyl and Het-C₀₋₆alkyl;

R¹⁰ is selected from the group consisting of: C₁₋₆alkyl,C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar—C₀₋₆alkyl and Het-C₀₋₆alkyl;

R¹¹ is selected from the group consisting of: H, C₁₋₆alkyl,Ar—C₀₋₆alkyl, C₃₋₆cycloalkyl-C₀₋₆alkyl, and Het-C₀₋₆alkyl;

R¹² is selected from the group consisting of: H, C₁₋₆alkyl,Ar—C₀₋₆alkyl, and Het-C₀₋₆alkyl;

R¹³ is selected from the group consisting of: H, C₁₋₆alkyl,Ar—C₀₋₆alkyl, and Het-C₀₋₆alkyl;

R′ is selected from the group consisting of: H, C₁₋₆alkyl, Ar—C₀₋₆alkyl,and Het-C₀₋₆alkyl;

R″ is selected from the group consisting of: H, C₁₋₆alkyl, Ar—C₀₋₆alkyl,or Het-C₀₋₆alkyl;

R′″ is C₁₋₆alkyl;

X is selected from the group consisting of: CH₂, S, and O;

Z is selected from the group consisting of: C(O) and CH₂;

n is an integer from 1 to 5;

and pharmaceutically acceptable salts, hydrates and solvates thereof.

In compounds of Formula I, when R¹ is

R³ is selected from the group consisting of: H, C₁₋₆alkyl,C₃₋₆cycloalkyl-C₀₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, Het-C₀₋₆alkyl,Ar—C₀₋₆alkyl, Ar—ArC₀₋₆alkyl, Ar—HetC₀₋₆alkyl, Het-ArC₀₋₆alkyl, andHet-HetC₀₋₆alkyl. Preferably, R³ is Ar—ArC₀₋₆alkyl, more preferably3-isobutyl biphenyl.

In compounds of Formula I, when R¹ is

n is preferably 4, to provide 1-amino-1-acyl cyclohexane compounds. Thecycloalkyl ring may be unsubstituted or substituted with one or more ofC₁₋₆alkyl, C₃₋₆cycloalkyl-C₀₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,HetC₀₋₆alkyl, ArC₀₋₆alkyl, or halogen.

The cycloalkyl ring is more preferably unsubstituted.

In compounds of Formula I, when R¹ is

R³ is selected from the group consisting of: H, C₁₋₆alkyl,C₃₋₆cycloalkyl-C₀₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, Het-C₀₋₆alkyl,Ar—C₀₋₆alkyl, Ar—ArC₀₋₆alkyl, Ar—HetC₀₋₆alkyl, Het-ArC₀₋₆alkyl, andHet-HetC₀₋₆alkyl;

R³ is preferably selected from the group consisting of: H,C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar—C₀₋₆alkyl, and C₁₋₆alkyl;

R³ is more preferably selected from the group consisting of:

H, methyl, ethyl, n-propyl, prop-2-yl, n-butyl, isobutyl, but-2-yl,cyclopropylmethyl, cyclohexylmethyl, 2-methanesulfinyl-ethyl,1-hydroxyethyl, toluyl, naphthalen-2-ylmethyl, benzyloxymethyl, andhydroxymethyl.

R³ is even more preferably selected from the group consisting of:toluyl, isobutyl and cyclohexylmethyl.

R³ is most preferably isobutyl.

R⁴ is selected from the group consisting of: H, C₁₋₆alkyl,C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar—C₀₋₆alkyl, Het-C₀₋₆alkyl, R⁵C(O)—, R⁵C(S)—,R⁵SO₂—, R⁵OC(O)—, R⁵R¹²NC(O)—, and R⁵R¹²NC(S)—.

R⁴ is preferably selected from the group consisting of: R⁵OC(O)—,R⁵C(O)— and R⁵SO₂—.

R⁴ is most preferably R⁵C(O)—.

In some embodiments, R⁴ is preferably methanesulfonyl.

R⁵ is selected from the group consisting of: H, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₆cycloalkyl-C₀₋₆alkyl, C₂₋₆alkanonyl, Ar—C₀₋₆alkyl orHet-C₀₋₆alkyl.

Preferably R⁵ is selected from the group consisting of: C₁₋₆alkyl,C₂₋₆alkenyl, C₃₋₆cycloalkyl-C₀₋₆alkyl, C₂₋₆alkanonyl, Ar—C₀₋₆alkyl andHet-C₀₋₆alkyl.

More preferably, and especially when R⁴ is R⁵C(O)—, R⁵ is selected fromthe group consisting of:

methyl, especially halogenated methyl, more especially trifluoromethyl,especially C₁₋₆alkoxy and aryloxy substituted methyl, more especiallyphenoxy-methyl, 4-fluoro-phenoxy-methyl, especially heterocyclesubstituted methyl, more especially 2-thiophenyl-methyl;

butyl, especially aryl substituted butyl, more especially4-(4-methoxy)phenyl-butyl;

isopentyl;

cyclohexyl;

pentanonyl, especially 4-pentanonyl;

butenyl, especially aryl substituted butenyl, more especially4,4-bis(4-methoxyphenyl)-but-3-enyl;

phenyl, especially phenyl substituted with one or more halogens, moreespecially 3,4-dichlorophenyl and 4-fluorophenyl, especially phenylsubstituted with one or more C₁₋₆ alkoxy or aryloxy groups, moreespecially 3,4-dimethoxy-phenyl, 3-benzyloxy-4-methoxy-phenyl,especially phenyl substituted with one or more sulfonyl groups, moreespecially 4-methanesulfonyl-phenyl;

benzyl;

naphthalenyl, especially naphthylen-2-yl;

benzo[1,3]dioxolyl, especially benzo[1,3]dioxol-5-yl,

furanyl, especially furan-2-yl, especially substituted furanyl, such as5-nitro-furan-2-yl, 5-(4-nitrophenyl)-furan-2-yl,5-(3-trifluoromethyl-phenyl)-furan-2-yl, more especially halogensubstituted furanyl, even more especially 5-bromo-furan-2-yl, moreespecially aryl substituted furanyl, even more especially5-(4-chloro-phenyl)-furan-2-yl;

tetrahydrofuranyl, especially tetrahydrofuran-2-yl;

benzofuranyl, especially benzofuran-2-yl, and especially C₁₋₆alkoxysubstituted benzofuranyl, more especially 5-(2-piperazin-4-carboxylicacid tert-butyl ester-ethoxy)benzofuran-2-yl,5-(2-morpholino-4-yl-ethoxy)-benzofuran-2-yl,5-(2-piperazin-1-yl-ethoxy)benzofuran-2-yl,5-(2-cyclohexyl-ethoxy)-benzofuran-2-yl; 7-methoxy-benzofuran-2-yl,5-methoxy-benzofura-2-yl, 5,6-dimethoxy-benzofuran-2-yl, especiallyhalogen substituted benzofuranyl, more especially5-fluoro-benzofuran-2-yl, 5,6-difluoro-benzofuran-2-yl, especiallyC₁₋₆alkyl substituted benzofuranyl, most especially3-methyl-benzofuran-2-yl;

benzo[b]thiophenyl, especially benzo[b]thiophen-2-yl; especiallyC₁₋₆alkoxy substituted benzo[b]thiophenyl, more especially5,6-dimethoxy-benzo[b]thiophen-2-yl;

quinolinyl, especially quinolin-2-yl, quinolin-3-yl, quinolin-4-yl,quinolin-6-yl, and quinolin-8-yl;

quinoxalinyl, especially quinoxalin-2-yl;

1,8 naphthyridinyl, especially 1,8 naphthyridin-2-yl;

indolyl, especially indol-2-yl, especially indol-6-yl, indol-5-yl,especially C₁₋₆alkyl substituted indolyl, more especiallyN-methyl-indol-2-yl;

pyridinyl, especially pyridin-2-yl, pyridin-5-yl, especially1-oxy-pyridin-2-yl, especially C₁₋₆alkyl substituted pyridinyl, moreespecially 2-methyl-pyridin-5-yl;

furo[3,2-b]pyridinyl, especially furo[3,2-b]pyridin-2-yl, and C₁₋₆alkylsubstituted furo[3,2-b]pyridinyl, especially3-methyl-furo[3,2-b]pyridin-2-yl;

thiophenyl, especially thiophen-3-yl, especially C₁₋₆alkyl substitutedthiophenyl, more especially 5-methyl-thiophen-2-yl, especially halogensubstituted thiophenyl, more especially 4,5-dibromo-thiophen-2-yl;

thieno[3,2-b]thiophene, especially thieno[3,2-b]thiophene-2-yl, moreespecially C₁₋₆alkyl substituted thieno[3,2-b]thiophene-2-yl, moreespecially 5-tert-butyl-3-methyl-thieno[3,2-b]thiophene-2-yl;

isoxazolyl, especially isoxazol-4-yl, especially C₁₋₆alkyl substitutedisoxazolyl, more especially 3,5-dimethyl-isoxazol-4-yl; and

oxazolyl, especially oxazol-4-yl, more especially 5-methyl-2-phenyloxazol-4-yl, 2-phenyl-5-trifluoromethyl-oxazol-4-yl;

When R⁴ is R⁵SO₂, R⁵ is preferably pyridin-2-yl or 1-oxo-pyridin-2-yl.

R′ is selected from the group consisting of: H, C₁₋₆alkyl, Ar—C₀₋₆alkyl,and Het-C₀₋₆alkyl.

Preferably R′ selected from the group consisting of: H andnaphthalen-2-yl-methyl.

Most preferably R′ is H.

R″ selected from the group consisting of: H, C₁₋₆alkyl, Ar—C₀₋₆alkyl,and Het-C₀₋₆alkyl.

Most preferably R″ is H.

R′″ is:

C₁₋₆alkyl, especially selected from the group consisting of: methyl,ethyl, propyl, butyl, pentyl and hexyl, more especially methyl;

preferably 5-, 6- or 7-C₁₋₆alkyl, especially selected from the groupconsisting of: 5-, 6- or 7-methyl, -ethyl, -propyl, -butyl, -pentyl and-hexyl, more especially 5-, 6- or 7-methyl;

more preferably 6- or 7-C₁₋₆alkyl, especially selected from the groupconsisting of: 6- or 7-methyl, -ethyl, -propyl, -butyl, -pentyl and-hexyl, more especially 6- or 7-methyl;

yet more preferably cis-7-C₁₋₆alkyl as shown in Formula Ia:

wherein R′″ is C₁₋₆alkyl, especially selected from the group consistingof: methyl, ethyl, propyl, butyl, pentyl and hexyl;

most preferably cis-7-methyl, as shown in Formula Ia wherein R′″ ismethyl.

In compounds of Formula I, R² is selected from the group consisting of:H, C₁₋₆alkyl, C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar—C₀₋₆alkyl, Het-C₀₋₆alkyl,R⁹C(O)—, R⁹C(S)—, R⁹SO₂—, R⁹OC(O)—, R⁹R¹¹NC(O)—, R⁹R¹¹NC(S)—,R⁹R¹¹NSO₂—,

Preferably R² is selected from the group consisting of: Ar—C₀₋₆alkyl,R⁹C(O)—, R⁹SO₂, R⁹R¹¹NC(O)—, and

More preferably, R² is selected from the group consisting of:Ar—C₀₋₆alkyl, R⁹C(O)—, and R⁹SO₂.

Most preferably R² is R⁹SO₂.

In such embodiments:

R⁶ is selected from the group consisting of: H, C₁₋₆alkyl, Ar—C₀₋₆alkyl,or Het-C₀₋₆alkyl, preferably H.

R⁷ is selected from the group consisting of: H, C₁₋₆alkyl,C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar—C₀₋₆alkyl, Het-C₀₋₆alkyl, R¹⁰C(O)—,R¹⁰C(S)—, R¹⁰SO₂—, R¹⁰OC(O)—, R¹⁰R¹³NC(O)—, R¹⁰R¹³NC(S)—, R⁷ ispreferably R¹⁰OC(O).

R⁸ is selected from the group consisting of: H, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, HetC₀₋₆alkyl and ArC₀₋₆alkyl; preferably C₁₋₆alkyl, morepreferably isobutyl.

R⁹ is selected from the group consisting of: C₁₋₆alkyl,C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar—C₀₋₆alkyl, and Het-C₀₋₆alkyl.

More preferably, R⁹ is selected from the group consisting of:

methyl;

ethyl, especially C₁₋₆alkyl-substituted ethyl, more especially2-cyclohexyl-ethyl;

butyl, especially C₁₋₆butyl, more especially 3-methylbutyl;

tert-butyl, particularly when R² is R⁹OC(O);

isopentyl;

phenyl, especially halogen substituted phenyl, more especially3,4-dichlorophenyl, 4-bromophenyl, 2-fluorophenyl, 4-fluorophenyl,3-chlorophenyl, 4-chlorophenyl, especially C₁₋₆alkoxy phenyl, moreespecially 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl,especially cyanophenyl, more especially 2-cyanophenyl;

toluyl, especially Het-substituted toluyl, more especially3-(pyridin-2-yl)toluyl;

naphthylenyl, especially naphthylen-2-yl;

benzoyl, especially 2-benzoyl;

benzo[1,3]dioxolyl, especially benzo[1,3]dioxol-5-yl;

benzo[1,2,5]oxadiazolyl, especially benzo[1,2,5]oxadiazol-4-yl;

pyridinyl, especially pyridin-2-yl, pyridin-3-yl, especially1-oxy-pyridinyl, more especially 1-oxy-pyridin-2-yl, 1-oxy-pyridin-3-yl;especially C₁₋₆alkylpyridinyl, more especially 3-methyl-pyridin-2-yl,6-methyl-pyridin-2-yl,

thiophene, especially thiophene-2-yl;

thiazolyl, especially thiazol-2-yl;

1H-imidazolyl, especially 1H-imidazol-2-yl, 1H-imidazol-4-yl, moreespecially C₁₋₆alkyl substituted imidazolyl, even more especially1-methyl-1H-imidazol-2-yl, 1-methyl-1H-imidazol-4-yl;

1H-[1,2,4]triazolyl, especially 1H-[1,2,4]triazol-3-yl, more especiallyC₁₋₆alkyl substituted 1H-[1,2,4]triazolyl, even more especially5-methyl-1H-[1,2,4]triazol-3-yl; and

quinolinyl.

When R² is R⁹SO₂, R⁹ is most preferably selected from the groupconsisting of: pyridin-2-yl and 1-oxy-pyridin-2-yl.

R¹⁰ is selected from the group consisting of: C₁₋₆alkyl,C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar—C₀₋₆alkyl or Het-C₀₋₆alkyl; preferablyC₁₋₆alkyl, Ar—C₀₋₆alkyl and Het-C₀₋₆alkyl.

Z is selected from the group consisting of: C(O) and CH₂.

R² is also preferably:

H;

toluyl;

aryl substituted ethyl, especially 2-phenyl ethyl,2-[3-(pyridin-2-yl)phenyl]ethyl.

Compounds of Formula I where R″ is H and and R′″ is methyl arepreferred.

More preferred are compounds of Formula I wherein:

R¹ is

R² is selected from the group consisting of: H, C₁₋₆alkyl,C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar—C₀₋₆alkyl, Het-C₀₋₆alkyl, R⁹C(O)—, R⁹C(S)—,R⁹SO₂—, R⁹OC(O)—, R⁹R¹¹NC(O)—, R⁹R¹¹NC(S)—, R⁹(R¹¹)NSO₂—,

R³ is selected from the group consisting of: H, C₁₋₆alkyl,C₃₋₆cycloalkyl-C₀₋₆alkyl, and Ar—C₀₋₆alkyl;

R⁴ is selected from the group consisting of: R⁵C(O)—, R⁵SO₂—, andR⁵OC(O)—;

R⁵ is selected from the group consisting of: C₁₋₆alkyl, C₂₋₆alkenyl,C₃₋₆cycloalkyl-C₀₋₆alkyl, C₂₋₆alkanonyl, Ar—C₀₋₆alkyl and Het-C₀₋₆alkyl;

R⁶ is selected from the group consisting of: H, C₁₋₆alkyl, Ar—C₀₋₆alkyl,and Het-C₀₋₆alkyl;

R⁷ is selected from the group consisting of: H, C₁₋₆alkyl,C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar—C₀₋₆alkyl, Het-C₀₋₆alkyl, R¹⁰C(O)—,R¹⁰C(S)—, R¹⁰SO₂—, R¹⁰OC(O)—, R¹⁰R¹³NC(O)—, and R¹⁰R¹³NC(S)—;

R⁸ is selected from the group consisting of: H, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, HetC₀₋₆alkyl and ArC₀₋₆alkyl;

R⁹ is selected from the group consisting of: C₁₋₆alkyl,C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar—C₀₋₆alkyl and Het-C₀₋₆alkyl;

R¹⁰ is selected from the group consisting of: C₁₋₆alkyl,C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar—C₀₋₆alkyl and Het-C₀₋₆alkyl;

R¹¹ is selected from the group consisting of: H, C₁₋₆alkyl,Ar—C₀₋₆alkyl, C₃₋₆cycloalkyl-C₀₋₆alkyl, and Het-C₀₋₆alkyl;

R¹² is selected from the group consisting of: H, C₁₋₆alkyl,Ar—C₀₋₆alkyl, and Het-C₀₋₆alkyl;

R¹³ is selected from the group consisting of: H, C₁₋₆alkyl,Ar—C₀₋₆alkyl, and Het-C₀₋₆alkyl;

R′ is H;

R″ is H;

R′″ is selected from the group consisting of:

C₁₋₆alkyl, especially selected from the group consisting of: methyl,ethyl, propyl, butyl, pentyl and hexyl, more especially methyl;

preferably 5-, 6- or 7-C₁₋₆alkyl, especially selected from the groupconsisting of: 5-, 6- or 7-methyl, -ethyl, -propyl, -butyl, -pentyl and-hexyl, more especially 5-, 6- or 7-methyl;

more preferably 6- or 7-C₁₋₆alkyl, especially selected from the groupconsisting of: 6- or 7-methyl, -ethyl, -propyl, -butyl, -pentyl and-hexyl, more especially 6- or 7-methyl;

yet more preferably cis-7-C₁₋₆alkyl as shown in Formula Ia:

wherein R′″ is C₁₋₆alkyl, especially selected from the group consistingof: methyl, ethyl, propyl, butyl, pentyl and hexyl;

most preferably cis-7-methyl, as shown in Formula Ia wherein R′″ ismethyl; and

Z is selected from the group consisting of: C(O) and CH₂.

Particularly preferred are such compounds wherein R³ is isobutyl.

Still more preferred are compounds of Formula I wherein:

R¹ is

R² is selected from the group consisting of: Ar—C₀₋₆alkyl, R⁹C(O)—,R⁹SO₂, R⁹R¹¹NC(O)—, and

R³ is selected from the group consisting of: H, C₁₋₆alkyl,C₃₋₆cycloalkyl-C₀₋₆alkyl, and Ar—C₀₋₆alkyl;

R⁴ is selected from the group consisting of: R⁵OC(O)—, R⁵C(O)— andR⁵SO₂—;

R⁵ is selected from the group consisting of: C₁₋₆alkyl, C₂₋₆alkenyl,C₃₋₆cycloalkyl-C₀₋₆alkyl, C₂₋₆alkanonyl, Ar—C₀₋₆alkyl and Het-C₀₋₆alkyl;

R⁶ is H;

R⁷ is R¹⁰OC(O);

R⁸ is C₁₋₆alkyl;

R⁹ is selected from the group consisting of: C₁₋₆alkyl,C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar—C₀₋₆alkyl and Het-C₀₋₆alkyl;

R¹⁰ is selected from the group consisting of: C₁₋₆alkyl, Ar—C₀₋₆alkyland Het-C₀₋₆alkyl;

R¹¹ is selected from the group consisting of: C₁₋₆alkyl,C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar—C₀₋₆alkyl and Het-C₀₋₆alkyl;

R′ is H;

R″ is H;

R′″ is methyl, preferably 5-, 6- or 7-methyl, more preferably 6- or7-methyl, most preferably cis-7-methyl, as shown in Formula Ia:

wherein R′″ is methyl; and

Z is selected from the group consisting of: C(O) and CH₂.

Even more preferred are such compounds of Formula I wherein R² isselected from the group consisting of: Ar—C₀₋₆alkyl, R⁹C(O)—, R⁹SO₂.

Yet more preferred are compounds of Formula I wherein:

R¹ is

R² is selected from the group consisting of: Ar—C₀₋₆alkyl, R⁹C(O)— andR⁹SO₂;

R³ is selected from the group consisting of: H, methyl, ethyl, n-propyl,prop-2-yl, n-butyl, isobutyl, but-2-yl, cyclopropylmethyl,cyclohexylmethyl, 2-methanesulfinyl-ethyl, 1-hydroxyethyl, toluyl,naphthalen-2-ylmethyl, benzyloxymethyl, and hydroxymethyl;

R⁴ is R⁵C(O)—;

R⁵ is selected from the group consisting of: methyl, especiallyhalogenated methyl, more especially trifluoromethyl, especiallyC₁₋₆alkoxy and aryloxy substituted methyl, more especiallyphenoxy-methyl, 4-fluoro-phenoxy-methyl, especially heterocyclesubstituted methyl, more especially 2-thiophenyl-methyl;

butyl, especially aryl substituted butyl, more especially4-(4-methoxy)phenyl-butyl;

isopentyl;

cyclohexyl;

pentanonyl, especially 4-pentanonyl;

butenyl, especially aryl substituted butenyl, more especially4,4-bis(4-methoxyphenyl)-but-3-enyl;

phenyl, especially phenyl substituted with one or more halogens, moreespecially 3,4-dichlorophenyl and 4-fluorophenyl, especially phenylsubstituted with one or more C₁₋₆alkoxy or aryloxy groups, moreespecially 3,4-dimethoxy-phenyl, 3-benzyloxy-4-methoxy-phenyl,especially phenyl substituted with one or more sulfonyl groups, moreespecially 4-methanesulfonyl-phenyl;

benzyl;

naphthylen-2-yl;

benzo[1,3]dioxolyl, especially benzo[1,3]dioxol-5-yl,

furanyl, especially furan-2-yl, especially substituted furanyl, such as5-nitro-furan-2-yl, 5-(4-nitrophenyl)-furan-2-yl,5-(3-trifluoromethyl-phenyl)-furan-2-yl, more especially halogensubstituted furanyl, even more especially 5-bromo-furan-2-yl, moreespecially aryl substituted furanyl, even more especially5-(4-chloro-phenyl)-furan-2-yl;

tetrahydrofuran-2-yl;

benzofuranyl, especially benzofuran-2-yl, and especially C₁₋₆alkoxysubstituted benzofuranyl, more especially 5-(2-piperazin-4-carboxylicacid tert-butyl ester-ethoxy)benzofuran-2-yl,5-(2-morpholino-4-yl-ethoxy)-benzofuran-2-yl,5-(2-piperazin-1-yl-ethoxy)benzofuran-2-yl,5-(2-cyclohexyl-ethoxy)-benzofuran-2-yl, 7-methoxy-benzofuran-2-yl,5-methoxy-benzofuran-2-yl, 5,6-dimethoxy-benzofuran-2-yl, especiallyhalogen substituted benzofuranyl, more especially5-fluoro-benzofuran-2-yl, 5,6-difluoro-benzofuran-2-yl, especiallyC₁₋₆alkyl substituted benzofuranyl, most especially3-methyl-benzofuran-2-yl;

benzo[b]thiophenyl, especially benzo[b]thiophen-2-yl; especiallyC₁₋₆alkoxy substituted benzo[b]thiophenyl, more especially5,6-dimethoxy-benzo[b]thiophen-2-yl;

quinolinyl, especially quinolin-2-yl, quinolin-3-yl, quinolin-4-yl,quinolin-6-yl, and quinolin-8-yl;

quinoxalinyl, especially quinoxalin-2-yl;

1,8 naphthyridinyl, especially 1,8 naphthyridin-2-yl;

indolyl, especially indol-2-yl, especially indol-6-yl, indol-5-yl,especially C₁₋₆alkyl substituted indolyl, more especiallyN-methyl-indol-2-yl;

pyridinyl, especially pyridin-2-yl, pyridin-5-yl, especially1-oxy-pyridin-2-yl, especially C₁₋₆alkyl substituted pyridinyl, moreespecially 2-methyl-pyridin-5-yl;

furo[3,2-b]pyridinyl, especially furo[3,2-b]pyridin-2-yl, and C₁₋₆alkylsubstituted furo[3,2-b]pyridinyl, especially3-methyl-furo[3,2-b]pyridin-2-yl;

thiophenyl, especially thiophen-3-yl, especially C₁₋₆alkyl substitutedthiophenyl, more especially 5-methyl-thiophen-2-yl, especially halogensubstituted thiophenyl, more especially 4,5-dibromo-thiophen-2-yl;

thieno[3,2-b]thiophene, especially thieno[3,2-b]thiophene-2-yl, moreespecially C₁₋₆alkyl substituted thieno[3,2-b]thiophene-2-yl, moreespecially 5-tert-butyl-3-methyl-thieno[3,2-b]thiophene-2-yl;

isoxazolyl, especially isoxazol-4-yl, especially C₁₋₆alkyl substitutedisoxazolyl, more especially 3,5-dimethyl-isoxazol-4-yl; and

oxazolyl, especially oxazol-4-yl, more especially 5-methyl-2-phenyloxazol-4-yl, 2-phenyl-5-trifluoromethyl-oxazol-4-yl;

R⁹ is selected from the group consisting of:

methyl;

ethyl, especially C₁₋₆alkyl-substituted ethyl, more especially2-cyclohexyl-ethyl;

butyl, especially C₁₋₆butyl, more especially 3-methylbutyl;

tert-butyl, particularly when R² is R⁹OC(O);

isopentyl;

phenyl, especially halogen substituted phenyl, more especially3,4-dichlorophenyl, 4-bromophenyl, 2-fluorophenyl, 4-fluorophenyl,3-chlorophenyl, 4-chlorophenyl, especially C₁₋₆alkoxy phenyl, moreespecially 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl,especially cyanophenyl, more especially 2-cyanophenyl;

toluyl, especially Het-substituted toluyl, more especially3-(pyridin-2-yl)toluyl;

naphthylene, especially naphthyl-2-ene;

benzoyl, especially 2-benzoyl;

benzo[1,3]dioxolyl, especially benzo[1,3]dioxol-5-yl;

benzo[1,2,5]oxadiazolyl, especially benzo[1,2,5]oxadiazol-4-yl;

pyridinyl, especially pyridin-2-yl, pyridin-3-yl, especiallyl-oxy-pyridinyl, more especially 1-oxy-pyridin-2-yl, 1-oxy-pyridin-3-yl;especially C₁₋₆alkylpyridinyl, more especially 3-methyl-pyridin-2-yl,6-methyl-pyridin-2-yl, thiophenyl, especially thiophene-2-yl;

thiazolyl, especially thiazol-2-yl;

1H-imidazolyl, especially 1H-imidazol-2-yl(74), 1H-imidazol-4-yl, moreespecially C₁₋₆alkyl substituted imidazolyl, even more especially1-methyl-1H-imidazol-2-yl, 1-methyl-1H-imidazol-4-yl; and

1H-[1,2,4]triazolyl, especially 1H-[1,2,4]triazol-3-yl, more especiallyC₁₋₆alkyl substituted 1H-[1,2,4]triazolyl, even more especially5-methyl-1H-[1,2,4]triazol-3-yl; and

quinolinyl;

R′ is H;

R″ is H; and

R′″ is methyl, preferably 5-, 6- or 7-methyl, more preferably 6- or7-methyl, most preferably cis-7-methyl, as shown in Formula Ia:

wherein R′″ is methyl.

Even yet more preferred are compounds of Formula I wherein:

R¹ is

R² is R⁹SO₂;

R³ is C₁₋₆alkyl;

R⁴ is R⁵C(O);

R⁵ is Het-C₀₋₆alkyl;

R⁹ is Het-C₀₋₆alkyl;

R′ is H;

R″ is H; and

R′″ is selected from the group consisting of: 5-, 6- or 7-methyl,preferably 6- or 7-methyl, most preferably cis-7-methyl, as shown inFormula Ia:

wherein R′″ is methyl.

Still yet more preferred are compounds of Formula I wherein:

R¹ is

R² is R⁹SO₂;

R³ is isobutyl;

R⁴ is R⁵C(O);

R⁵ is selected from the group consisting of: 5-methoxybenzofuran-2-yl,benzo[b]thiophen-2-yl, 3-methyl-benzofuran-2-yl,thieno[3,2-b]thiophen-2-yl, benzofuran-2-yl, furo[3,2-b]pyridin-2-yl,and 3-methyl-furo[3,2-b]pyridin-2-yl; preferably benzofuran-2-yl,furo[3,2-b]pyridin-2-yl, and 3-methyl-furo[3,2-b]pyridin-2-yl; mostpreferably benzofuran-2-yl.

R⁹ is selected from the group consisting of: pyridin-2-yl and1-oxy-pyridin-2-yl, preferably pyridin-2-yl.

R′ is H;

R″ is H; and

R′″ is selected from the group consisting of: 5-, 6- or 7-methyl,preferably 6- or 7-methyl, most preferably cis-7-methyl, as shown inFormula Ia:

wherein R′″ is methyl.

Compounds of Formula I selected from the following group areparticularly preferred embodiments of the present invention:

-   5-methoxy-benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[(4S,6S)-6-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide:

-   5-methoxy-benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[(4R,6R)-6-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide:

-   benzo[b]thiophene-2-carboxylic acid    {(S)-1-[(4S,6S)-6-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide:

-   benzo[b]thiophene-2-carboxylic acid    {(S)-1-[(4R,6R)-6-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide:

-   3-methyl-benzofuran-2-carboxylic acid    {(S)-1-[(4S,6S)-6-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl)}-amide:

-   3-methyl-benzofuran-2-carboxylic acid    {(S)-1-[(4R,6R)-6-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide:

-   thieno[3,2-b]thiophene-2-carboxylic acid    {(5)-1-[(4S,68)-6-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide:

-   thieno[3,2-b]thiophene-2-carboxylic acid    {(S)-1-[(4R,6R)-6-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide:

-   benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide:

-   benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[(4R,7S)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide:

-   benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[(4S,7S)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide:

-   benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[(4R,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide:

-   furo[3,2-b]pyridine-2-carboxylic acid    {(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo    1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide:

-   2,2,4-trideutero-furo[3,2-b]pyridine-2-carboxylic acid    {(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide:

-   3-methyl-furo[3,2-b]pyridine-2-carboxylic acid    {(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide:

-   2,2,4-trideutero-3-methyl-1-furo[3,2-b]pyridine-2-carboxylic acid    {(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide:

-   quinoline-6-carboxylic acid    {(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

-   quinoline-3-carboxylic acid    {(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

-   5-methoxy-benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

-   3-methyl-benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

-   thieno[3,2-b]thiophene-2-carboxylic acid    {(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

-   quinoxaline-2-carboxylic acid    {(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

-   thieno[3,2-b]thiophene-2-carboxylic acid    {(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

-   3-methyl-benzofuran-2-carboxylicacid    {(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

-   benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

-   quinoline-2-carboxylic acid    {(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

-   5,6-difluoro-benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

-   5-fluoro-3-methyl-benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

-   5-fluoro-benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

-   3-methyl-furo[3,2-b]]pyridine-2-carboxylic acid    {(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

-   cyclohexanecarboxylic acid    {(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

-   (S)-2-(2-cyclohexyl-ethanoylamino)-4-methyl-pentanoic acid    [(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-yl]-amide

-   (S)-2-(3-cyclohexyl-propanoylamino)-4-methyl-pentanoic acid    [(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-yl]-amide

-   (S)-2-(4-cyclohexyl-butanoylamino)-4-methyl-pentanoic acid    [(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-yl]-amide

-   (S)-2-(5-cyclohexyl-pentanoylamino)-4-methyl-pentanoic acid    [(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-yl]-amide

-   benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(5-trifluoromethyl-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

-   5-fluoro-benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(5-trifluoromethyl-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

-   thieno[3,2-b]thiophene-2-carboxylic acid    {(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(5-trifluoromethyl-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

-   benzofuran-2-carboxylic acid    {1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-cyclohexyl}-amide

-   thiophene-3-carboxylic acid    {(S)-3,3-dimethyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

-   furan-2-carboxylic acid    {(S)-3,3-dimethyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

-   thieno[3,2-b]thiophene-2-carboxylic acid    {(S)-3,3-dimethyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

-   benzofuran-2-carboxylic acid    {(S)-2-cyclohexyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide

-   furan-2-carboxylic acid    {(S)-2-cyclohexyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide

-   thiophene-3-carboxylic acid    {(S)-2-cyclohexyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide

-   3-methyl-furo[3,2-b]-pyridine-2-carboxylic acid    {(S)-2-cyclohexyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide

-   (2R,4aR,8aR)-octahydro-benzo[1,4]dioxine-2-carboxylic acid    [(S)-1-((4S,7R)-1-methanesulfonyl-7-methyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide

-   furan-2-carboxylic acid    [(S)-2-cyclohexyl-1-((4S,7R)-7-methyl-3-oxo-1-propyl-azepan-4-ylcarbamoyl)-ethyl]-amide

-   thiophene-3-carboxylic acid    [(S)-2-cyclohexyl-1-((4S,7R)-7-methyl-3-oxo-1-propyl-azepan-4-ylcarbamoyl)-ethyl]-amide

-   benzofuran-2-carboxylic acid    [(S)-2-cyclohexyl-1-((4S,7R)-7-methyl-3-oxo-1-propyl-azepan-4-ylcarbamoyl)-ethyl]-amide

-   1-(3-cyclohexyl-propanoylamino)-cyclohexanecarboxylic    acid((4S,7R)-1-cyclohexylmethyl-7-methyl-3-oxo-azepan-4-yl)-amide

-   benzofuran-2-carboxylic acid    [1-((4S,7R)-1-cyclohexylmethyl-7-methyl-3-oxo-azepan-4-ylcarbamoyl)-cyclohexyl]-amide

-   benzofuran-2-carboxylic acid    [(S)-3-methyl-1-((4S,7R)-7-methyl-3-oxo-1-propyl-azepan-4-ylcarbamoyl)-butyl]-amide

-   (2R,5S)-5-((S)-2-tert-butoxycarbonylamino-4-methyl-pentanoylamino)-2-methyl-6-oxo-azepane-1-carboxylic    acid benzyl ester

-   benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[(4S,7R)-7-methyl-1-(1-morpholin-4-yl-methanoyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}-amide

-   (S)-2-(3-cyclohexyl-propanoylamino)-4-methyl-pentanoic acid    [(4S,7R)-7-methyl-1-(1-morpholin-4-yl-methanoyl)-3-oxo-azepan-4-yl]-amide

-   (2R,5S)-5-{(S)-2-[(1-benzofuran-2-yl-methanoyl)-amino]-4-methyl-pentanoylamino}-2-methyl-6-oxo-azepane-1-carboxylic    acid (tetrahydro-pyran-4-yl)-amide

-   (S)-2-{[1-((2R,5S)-5-{(S)-2-[(1-benzofuran-2-yl-methanoyl)-amino]-4-methyl-pentanoylamino}-2-methyl-6-oxo-azepan-1-yl)-methanoyl]-amino}-4-methyl-pentanoic    acid methyl ester

-   (S)-2-{[1-((2R,5S)-5-{(S)-2-[(1-benzofuran-2-yl-methanoyl)-amino]-4-methyl-pentanoylamino}-2-methyl-6-oxo-azepan-1-yl)-methanoyl]-amino}-4-methyl-pentanoic    acid

-   (S)-2-{[1-(4-{(S)-2-[(1-benzofuran-2-yl-methanoyl)-amino]-4-methyl-pentanoylamino    1-3-oxo-azepan-1-yl)-methanoyl]-amino)-4-methyl-pentanoicacid methyl    ester

-   (S)-2-{[1-(4-{(S)-2-[(1-benzofuran-2-yl-methanoyl)-amino]-4-methyl-pentanoylamino}-3-oxo-azepan-1-yl)-methanoyl]-amino}-4-methyl-pentanoic    acid

-   (S)-4-methyl-2-{[1-((2R,5S)-2-methyl-5-{(S)-4-methyl-2-[(1-quinolin-8-yl-methanoyl)-amino]-pentanoylamino)-6-oxo-azepan-1-yl)-methanoyl]-amino}-pentanoic    acid methyl ester

-   (S)-4-methyl-2-{[1-((2R,5S)-2-methyl-5-{(S)-4-methyl-2-[(1-quinolin-8-yl-methanoyl)-amino]-pentanoylamino}-6-oxo-azepan-1-yl)-methanoyl]-amino}-pentanoic    acid

-   (R)-2-{[1-(4-{(S)-2-[(1-benzofuran-2-yl-methanoyl)-amino]-4-methyl-pentanoylamino}-3-oxo-azepan-1-yl)-methanoyl]-amino}-4-methyl-pentanoic    acid methyl ester

-   (R)-2-{[1-(4-{(S)-2-[(1-benzofuran-2-yl-methanoyl)-amino]-4-methyl-pentanoylamino}-3-oxo-azepan-1-yl)-methanoyl]-amino}-4-methyl-pentanoic    acid

-   4,5 (R,S)-benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[5-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide:

-   4S,5S-benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[5-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide:

-   4S,5R-benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[5-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide

-   4R,5R-benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[5-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide

-   4R,5S-benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[5-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}aide:

-   (R)-2-biphenyl-3-yl-4-methyl-pentanoic acid    [(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-yl]-amide:

-   3-Methyl-furo[3,2-b]-pyridine-2-carboxylic acid    {1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-cyclohexyl}-amide:

-   1-(3-cyclohexyl-propanoylamino)-cyclohexanecarboxylic acid    [(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-yl]-amide:

A most particularly preferred embodiment of the present invention isbenzofuran-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide:

Specific representative compounds of the present invention are set forthin Examples 1-64.

Compared to the corresponding 5- and 6-membered ring compounds, the7-membered ring compounds of the present invention are configurationallymore stable at the carbon center alpha to the ketone.

The present invention includes deuterated analogs of the inventivecompounds. Representative examples of such a deuterated compounds areset forth in Examples 7, 9 and 11. A representative synthetic route forthe deuterated compounds of the present invention is set forth in Scheme4, below. The deuterated compounds of the present invention exhibitsuperior chiral stability compared to the protonated isomer.

Definitions

The present invention includes all hydrates, solvates, complexes andprodrugs of the compounds of this invention. Prodrugs are any covalentlybonded compounds which release the active parent drug according toFormula I in vivo. If a chiral center or another form of an isomericcenter is present in a compound of the present invention, all forms ofsuch isomer or isomers, including enantiomers and diastereomers, areintended to be covered herein. Inventive compounds containing a chiralcenter may be used as a racemic mixture, an enantiomerically enrichedmixture, or the racemic mixture may be separated using well-knowntechniques and an individual enantiomer may be used alone. In cases inwhich compounds have unsaturated carbon-carbon double bonds, both thecis (Z) and trans (E) isomers are within the scope of this invention. Incases wherein compounds may exist in tautomeric forms, such as keto-enoltautomers, each tautomeric form is contemplated as being included withinthis invention whether existing in equilibrium or predominantly in oneform.

The meaning of any substituent at any one occurrence in Formula I or anysubformula thereof is independent of its meaning, or any othersubstituent's meaning, at any other occurrence, unless specifiedotherwise.

Abbreviations and symbols commonly used in the peptide and chemical artsare used herein to describe the compounds of the present invention. Ingeneral, the amino acid abbreviations follow the IUPAC-IUB JointCommission on Biochemical Nomenclature as described in Eur. J. Biochem.,158, 9 (1984).

“Proteases” are enzymes that catalyze the cleavage of amide bonds ofpeptides and proteins by nucleophilic substitution at the amide bond,ultimately resulting in hydrolysis. Such proteases include: cysteineproteases, serine proteases, aspartic proteases, and metalloproteases.The compounds of the present invention are capable of binding morestrongly to the enzyme than the substrate and in general are not subjectto cleavage after enzyme catalyzed attack by the nucleophile. Theytherefore competitively prevent proteases from recognizing andhydrolyzing natural substrates and thereby act as inhibitors.

The term “amino acid” as used herein refers to the D- or L-isomers ofalanine, arginine, asparagine, aspartic acid, cysteine, glutamine,glutamic acid, glycine, histidine, isoleucine, leucine, lysine,methionine, phenylalanine, proline, serine, threonine, tryptophan,tyrosine and valine.

“Hydrogen” or “H” includes all of its possible isotopes, including“deuterium” or “D” or “²H”; and “tritium” or “T” or “³H”.

“C₁₋₆alkyl” as applied herein is meant to include substituted andunsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl andt-butyl, pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simplealiphatic isomers thereof. C₁₋₆alkyl may be optionally substituted by amoiety selected from the group consisting of: OR¹⁴, C(O)R¹⁴, SR¹⁴,S(O)R¹⁴, NR142, R¹⁴NC(O)OR⁵, CO₂R¹⁴, CO₂NR¹⁴ ₂, N(C═NH)NH₂, Het,C₃₋₆cycloalkyl, and Ar; where R⁵ is selected from the group consistingof: H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl-C₀₋₆alkyl,Ar—C₀₋₆alkyl and Het-C₀₋₆alkyl; and R¹⁴ is selected from the groupconsisting of: H, C₁₋₆alkyl, Ar—C₀₋₆alkyl, and Het-C₀₋₆alkyl;

“C₃₋₆cycloalkyl” as applied herein is meant to include substituted andunsubstituted cyclopropane, cyclobutane, cyclopentane and cyclohexane.

“C₂₋₆ alkenyl” as applied herein means an alkyl group of 2 to 6 carbonswherein a carbon-carbon single bond is replaced by a carbon-carbondouble bond. C₂₋₆alkenyl includes ethylene, 1-propene, 2-propene,1-butene, 2-butene, isobutene and the several isomeric pentenes andhexenes. Both cis and trans isomers are included.

“C₂₋₆alkanonyl” as applied herein is meant to include unsubstituted andsubstituted acetyl, propanonyl, butanonyl, pentanonyl, and hexanonyl.

“C₂₋₆alkynyl” means an alkyl group of 2 to 6 carbons wherein onecarbon-carbon single bond is replaced by a carbon-carbon triple bond.C₂₋₆ alkynyl includes acetylene, 1-propyne, 2-propyne, 1-butyne,2-butyne, 3-butyne and the simple isomers of pentyne and hexyne.

“Halogen” means F, Cl, Br, and I.

“Ar” or “aryl” means phenyl or naphthyl, optionally substituted by oneor more of Ph-C₀₋₆alkyl; Het-C₀₋₆alkyl; C₁₋₆alkoxy; Ph-C₀₋₆alkoxy;Het-C₀₋₆alkoxy; OH, (CH₂)₁-6NR¹⁵R¹⁶; O(CH₂)₁₋₆NR¹⁵R¹⁶; C₁₋₆alkyl, OR¹⁷,N(R¹⁷)₂, SR¹⁷, CF₃, NO₂, CN, CO₂R¹⁷, CON(R¹⁷), F, Cl, Br or I; where R¹⁵and R¹⁶ are H, C₁₋₆alkyl, Ph-C₀₋₆alkyl, naphthyl-C₀₋₆alkyl orHet-C₀₋₆alkyl; and R¹⁷ is phenyl, naphthyl, or C₁₋₆alkyl.

“Ar—Ar” means aryl covalently linked to a second aryl. Examples of“Ar—Ar” include biphenyl or naphythyl-phenyl or phenyl-naphthyl.

As used herein “Het” or “heterocyclic” represents a stable 5- to7-membered monocyclic, a stable 7- to 10-membered bicyclic, or a stable11- to 18-membered tricyclic heterocyclic ring which is either saturatedor unsaturated, and which consists of carbon atoms and from one to threeheteroatoms selected from the group consisting of N, O and S, andwherein the nitrogen and sulfur heteroatoms may optionally be oxidized,and the nitrogen heteroatom may optionally be quaternized, and includingany bicyclic group in which any of the above-defined heterocyclic ringsis fused to a benzene ring. The heterocyclic ring may be attached at anyheteroatom or carbon atom which results in the creation of a stablestructure, and may optionally be substituted with one or two moietiesselected from C₀₋₆Ar, C₁₋₆alkyl, OR¹⁷, N(R¹⁷)₂, SR¹⁷, CF₃, NO₂, CN,CO₂R¹⁷, CON(R¹⁷), F, Cl, Br and I, where R¹⁷ is phenyl, naphthyl, orC₁₋₆alkyl. Examples of such heterocycles include piperidinyl,piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl,2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl,pyrazolyl, pyrazolidinyl, imidazolyl, pyridinyl, 1-oxo-pyridinyl,pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl,thiazolidinyl, thiazolinyl, thiazolyl, quinuclidinyl, indolyl,quinolinyl, quinoxalinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,benzoxazolyl, furanyl, benzofuranyl, thiophenyl, benzo[b]thiophenyl,thieno[3,2-b]thiophenyl, benzo[1,3]dioxolyl, 1,8 naphthyridinyl,pyranyl, tetrahydrofuranyl, tetrahydropyranyl, thienyl, benzoxazolyl,thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl, aswell as triazolyl, thiadiazolyl, oxadiazolyl, isothiazolyl, imidazolyl,pyridazinyl, pyrimidinyl, triazinyl and tetrazinyl which are availableby routine chemical synthesis and are stable. The term heteroatom asapplied herein refers to oxygen, nitrogen and sulfur.

“Ar—Het” means an aryl group covalently linked to a heterocycle.Examples of “Ar—Het” include phenyl-piperidine, phenyl-piperazine,phenyl-2-oxopiperazine, naphthyl-piperidine, naphthyl-piperazine, andnaphthyl-2-oxopiperazine.

“Het-Ar” means a heterocycle covalently linked to a aryl group. Examplesof such “Het-Ar” include piperidinyl-phenyl, piperazinyl-phenyl,2-oxopiperazinyl-phenyl, piperidinyl-naphthyl, piperazinyl-naphthyl, and2-oxopiperazinyl-naphthyl.

“Het-Het” means a heterocycle covalently linked to a second heterocycle.Examples of such “Het-Het” include bipyridine, pyridinyl-piperidine,pyridinyl-piperazine, pyridinyl-2-oxopiperazine, thiophenyl-piperidine,thiophenyl-piperazine, and thiophenyl-2-oxopiperazine.

Here and throughout this application the term C₀ denotes the absence ofthe substituent group immediately following; for instance, in the moietyArC₀₋₆alkyl, when C is 0, the substituent is Ar, e.g., phenyl.Conversely, when the moiety ArC₀₋₆alkyl is identified as a specificaromatic group, e.g., phenyl, it is understood that the value of C is 0.

Certain radical groups are abbreviated herein. t-Bu refers to thetertiary butyl radical, Boc refers to the t-butyloxycarbonyl radical,Fmoc refers to the fluorenylmethoxycarbonyl radical, Ph refers to thephenyl radical, Cbz refers to the benzyloxycarbonyl radical.

Certain reagents are abbreviated herein. m-CPBA refers to3-chloroperoxybenzoic acid, EDC refers toN-ethyl-N′(dimethylaminopropyl)-carbodiimide, DMF refers to dimethylformamide, DMSO refers to dimethyl sulfoxide, TEA refers totriethylamine, TFA refers to trifluoroacetic acid, and THF refers totetrahydrofuran.

Methods of Preparation

Compounds of the general formula I may be prepared in a fashionanalogous to that outlined in Schemes 1 to 8.

2-Methyl-pent-4-enoic acid ethyl ester is converted to aN-2-pyridinesulfonyl-azapine by reduction to the aldehyde, reductiveamination with allylamine, sulfonylation with 2-pyridyl sulfonylchloride, and olefin metathesis with Grubbs' catalyst. Epoxidation withmCPBA affords a mixture of epoxides that are separable by columnchromatography. The syn epoxide is converted into an amino alcohol byopening with sodium azide followed by reduction with triphenylphosphine.Acylation of the free amine with Boc-leucine and a coupling reagent suchas HBTU or EDC, followed by deprotection of the Boc group with HCl, andacylation with a variety of aromatic carboxylic acids and couplingreagents such as HBTU or EDC gives the intermediate alcohols. Finaloxidation with Dess-Martin periodinane and HPLC affords the desiredketones.

5-Hexen-2-one is converted to a N-carbobenzyloxy-azapine by reductiveamination with allylamine, protection with carbobenzyloxychloride, andolefin metathesis with Grubbs' catalyst. Epoxidation with mCPBA affordsa mixture of epoxides that are separable by column chromatography. Eachepoxide is converted into an amino alcohol by opening with sodium azidefollowed by reduction with triphenylphosphine. Acylation of the freeamine with Boc-leucine and a coupling reagent such as HBTU or EDC,followed by deprotection of the Cbz group by hydrogenolysis provides thesecondary amines which are in turn sulfonylated with 2-pyridinesulfonylchloride. Deprotection of the Boc groups with HCl and acylationwith a variety of aromatic carboxylic acids and coupling reagents suchas HBTU or EDC gives the intermediate alcohols. Final oxidation withDess-Martin periodinane and HPLC affords the desired ketones.

Carbobenyzloxy-D-alaninol (Cbz-D-alaninol) is first converted to aniodide, then is reacted with allyl Grignard with a copper (I) catalystor a similar allyl organometallic reagent. The amine is then alkylatedwith allyl iodide. Grubbs' catalyst is then used to form the azapinering by ring closing metathesis. Epoxidation of the alkene followed byseparation of the diastereomers followed by opening of the epoxide ofthe minor component with sodium azide provides the intermediate azidoalcohol. Reduction of the azide followed by acylation of the amine witha protected amino acid such as Boc-leucine, followed by deprotection ofthe Cbz gives the intermediate secondary amine, which is thensulfonylated with a sulfonyl chloride such as pyridine sulfonylchloride. Deprotection of the Boc group followed by acylation with anacylating agent such as quinoline-6-carboxylic acid, HBTU, NMM, andfinal oxidation of the secondary alcohol to the ketone with an oxidantsuch as sulfur trioxide-pyridine or Dess-Martin periodinane provides thedesired products.

Deuterated inhibitors can be prepared from the parent inhibitors such asbenzofuran-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amideby treating with a base such as triethyl amine and stirring for severaldays in a deteurated protic solvent such as CD₃OD: D₂O.

Intermediate(S)-3-Cyclohexyl-N-((3S,4S,7R)-3-hydroxy-7-methyl-azepan-4-yl)-2-methyl-propionamide,as described in Scheme 3 (using Boc-cyclohexylalanine instead ofBoc-L-leucine), is reductively aminated with an aldehyde or a ketonesuch as propionaldehyde, then treated with a reducing agent such assodium borohydride. Deprotection of the Boc group followed by acylationwith an acylating agent such as 2-furan carboxylic acid, HBTU, NMM, andfinal oxidation of the secondary alcohol to the ketone with an oxidantsuch as sulfur trioxide-pyridine provides the desired products.

Intermediate[(S)-1-((S)-3-Hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamicacid tert-butyl ester, as described in Scheme 3, is acylated with anisocyanate such as (S)-(−)-2-isocyanato-4-methylvaleric acid methylester. Deprotection of the Boc group followed by acylation with anacylating agent such as benzofuran-2-carboxylic acid, HBTU, NMM, andfinal oxidation of the secondary alcohol to the ketone with an oxidantsuch as Dess-Martin periodinane or sulfur trioxide-pyridine provides thedesired products.

The synthesis of the C-5 methyl azepinone, 4,5(R,S)-benzofuran-2-carboxylic acid{(S)-3-methyl-1-[5-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide,(Example 61) is outlined above in Scheme 7. Michael addition ofnitromethane to ethyl crotonate 7-1 followed by reduction of theintermediate ester with a reducing agent such as diisobutyl aluminumhydride (Dibal-H) provides the aldehyde 7-2. Reductive amination of 7-2with N-benzyl ethanolamine in the presence of a reducing agent such assodium triacetoxyborohydride provides the nitro-alcohol 7-3. Oxidationof 7-3 using an oxidant common to the art such as DMSO and oxalylchloride followed by treatment of the crude intermediate aldehyde with abase such as triethylamine effects the nitro-aldol reaction to give theazepanol 7-4. Reduction of the nitro group with zinc in the presence ofhydrochloric acid followed by coupling of the resulting amine withN-Boc-leucine in the presence of a coupling agent common to the art suchas EDC provides intermediate 7-5. Reductive removal of the N-benzylmoiety with hydrogen gas in the presence of a catalyst such as 10% Pd oncarbon followed by sulfonylation with a sulfonyl chloride in thepresence of a base such as N-methylmorpholine or triethyl amine providesthe sulfonamide intermediate 7-6. Removal of the N-Boc protecting groupunder acidic conditions followed by coupling of the resulting amine saltwith benzofuran-2-carboxylic acid and oxidation of the alcohol with anoxidant common to the art such as pyridine sulfur trioxide complex orDess-Martin periodinane provides the ketone 7. The individualdiastereomers of 7-7 may be separated by HPLC methods to providediastereomers 7-8,7-9, 7-10 and 7-11.

Intermediate (2R,5R,6R)-5-Amino-6-hydroxy-2-methyl-azepane-1-carboxylicacid benzyl ester (derived from the major epoxide of Scheme 3) isprotected with Boc anhydride. Then, the Cbz group is removed byhydrogenolysis. Sulfonylation is then accomplished with 2-pyridinesulfonyl chloride, and the Boc group is removed with hydrochloric acidin dioxane. The primary amine is then coupled with2-biphenyl-3-yl-4-methyl-pentanoic acid (as described in. J. Am. Chem.Soc. 1997, 120, 9114), then the secondary alcohol to the ketone with anoxidant such as Dess-Martin periodinane or sulfur trioxide-pyridine. Theazepanone is then epimerized using triethylamine in MeOH to provide amixture of diastereomers. The desired compound is obtained by separationof the diastereomers using chiral HPLC.

The starting materials used herein are commercially available aminoacids or are prepared by routine methods well known to those of ordinaryskill in the art and can be found in standard reference books, such asthe COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-VI (published byWiley-Interscience).

Coupling methods to form amide bonds herein are generally well known tothe art. The methods of peptide synthesis generally set forth byBodansky et al., THE PRACTICE OF PEPTIDE SYNTHESIS, Springer-Verlag,Berlin, 1984; E. Gross and J. Meienhofer, THE PEPTIDES, Vol. 1, 1-284(1979); and J. M. Stewart and J. D. Young, SOLID PHASE PEPTIDESYNTHESIS, 2d Ed., Pierce Chemical Co., Rockford, Ill., 1984. aregenerally illustrative of the technique and are incorporated herein byreference.

Synthetic methods to prepare the compounds of this invention frequentlyemploy protective groups to mask a reactive functionality or minimizeunwanted side reactions. Such protective groups are described generallyin Green, T. W, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, John Wiley &Sons, New York (1981). The term “amino protecting groups” generallyrefers to the Boc, acetyl, benzoyl, Fmoc and Cbz groups and derivativesthereof as known to the art. Methods for protection and deprotection,and replacement of an amino protecting group with another moiety arewell known.

Acid addition salts of the compounds of Formula I are prepared in astandard manner in a suitable solvent from the parent compound and anexcess of an acid, such as hydrochloric, hydrobromic, hydrofluoric,sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic ormethanesulfonic. Certain of the compounds form inner salts orzwitterions which may be acceptable. Cationic salts are prepared bytreating the parent compound with an excess of an alkaline reagent, suchas a hydroxide, carbonate or alkoxide, containing the appropriatecation; or with an appropriate organic amine. Cations such as Li⁺, Na⁺,K⁺, Ca⁺⁺, Mg⁺⁺ and NH₄ ⁺ are specific examples of cations present inpharmaceutically acceptable salts. Halides, sulfate, phosphate,alkanoates (such as acetate and trifluoroacetate), benzoates, andsulfonates (such as mesylate) are examples of anions present inpharmaceutically acceptable salts.

This invention also provides a pharmaceutical composition whichcomprises a compound according to Formula I and a pharmaceuticallyacceptable carrier, diluent or excipient. Accordingly, the compounds ofFormula I may be used in the manufacture of a medicament. Pharmaceuticalcompositions of the compounds of Formula I prepared as hereinbeforedescribed may be formulated as solutions or lyophilized powders forparenteral administration. Powders may be reconstituted by addition of asuitable diluent or other pharmaceutically acceptable carrier prior touse. The liquid formulation may be a buffered, isotonic, aqueoussolution. Examples of suitable diluents are normal isotonic salinesolution, standard 5% dextrose in water or buffered sodium or ammoniumacetate solution. Such formulation is especially suitable for parenteraladministration, but may also be used for oral administration orcontained in a metered dose inhaler or nebulizer for insufflation. Itmay be desirable to add excipients such as polyvinylpyrrolidone,gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol,sodium chloride or sodium citrate.

Alternately, these compounds may be encapsulated, tableted or preparedin an emulsion or syrup for oral administration. Pharmaceuticallyacceptable solid or liquid carriers may be added to enhance or stabilizethe composition, or to facilitate preparation of the composition. Solidcarriers include starch, lactose, calcium sulfate dihydrate, terra alba,magnesium stearate or stearic acid, talc, pectin, acacia, agar orgelatin. Liquid carriers include syrup, peanut oil, olive oil, salineand water. The carrier may also include a sustained release materialsuch as glyceryl monostearate or glyceryl distearate, alone or with awax. The amount of solid carrier varies but, preferably, will be betweenabout 20 mg to about 1 g per dosage unit. The pharmaceuticalpreparations are made following the conventional techniques of pharmacyinvolving milling, mixing, granulating, and compressing, when necessary,for tablet forms; or milling, mixing and filling for hard gelatincapsule forms. When a liquid carrier is used, the preparation will be inthe form of a syrup, elixir, emulsion or an aqueous or non-aqueoussuspension. Such a liquid formulation may be administered directly p.o.or filled into a soft gelatin capsule.

For rectal administration, the compounds of this invention may also becombined with excipients such as cocoa butter, glycerin, gelatin orpolyethylene glycols and molded into a suppository.

Novel Intermediates

Referring to the methods of preparing the compounds of Formula I setforth in Schemes 1-8 above, the skilled artisan will appreciate that thepresent invention includes all novel intermediates required to make thecompounds of Formula I. In particular, the present invention providesthe compounds of Formula II:

wherein:

R¹ is selected from the group consisting of:

R² is selected from the group consisting of: H, C₁₋₆alkyl,C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar—C₀₋₆alkyl, Het-C₀₋₆alkyl, R⁹C(O)—, R⁹C(S)—,R⁹SO₂—, R⁹OC(O)—, R⁹R¹¹NC(O)—, R⁹R¹¹NC(S)—, R⁹(R¹¹)NSO₂—

R³ is selected from the group consisting of: H, C₁₋₆alkyl,C₃₋₆cycloalkyl-C₀₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, HetC₀₋₆alkyl,ArC₀₋₆alkyl, Ar—ArC₀₋₆alkyl, Ar—HetC₀₋₆alkyl, Het-ArC₀₋₆alkyl, andHet-HetC₀₋₆alkyl;

R³ and R′ may be connected to form a pyrrolidine, piperidine ormorpholine ring;

R⁴ is selected from the group consisting of: H, C₁₋₆alkyl,C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar—C₀₋₆alkyl, Het-C₀₋₆alkyl, R⁵C(O)—, R⁵C(S)—,R⁵SO₂—, R⁵OC(O)—, R⁵R¹²NC(O)—, and R⁵R¹²NC(S)—;

R⁵ is selected from the group consisting of: H, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar—C₀₋₆alkyl and Het-C₀₋₆alkyl;

R⁶ is selected from the group consisting of: H, C₁₋₆alkyl, Ar—C₀₋₆alkyl,or Het-C₀₋₆alkyl;

R⁷ is selected from the group consisting of: H, C₁₋₆alkyl,C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar—C₀₋₆alkyl, Het-C₀₋₆alkyl, R¹⁰C(O)—,R¹⁰C(S)—, R¹⁰SO₂—, R¹⁰OC(O)—, R¹⁰R¹³NC(O)—, and R¹⁰R¹³NC(S)—;

R⁸ is selected from the group consisting of: H, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, HetC₀₋₆alkyl and ArC₀₋₆alkyl;

R⁹ is selected from the group consisting of: C₁₋₆alkyl,C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar—C₀₋₆alkyl and Het-C₀₋₆alkyl;

R¹⁰ is independently selected from the group consisting of: C₁₋₆alkyl,C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar—C₀₋₆alkyl and Het-C₀₋₆alkyl;

R¹¹ is selected from the group consisting of: H, C₁₋₆alkyl,C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar—C₀₋₆alkyl, and Het-C₀₋₆alkyl;

R¹² is selected from the group consisting of: H, C₁₋₆alkyl,Ar—C₀₋₆alkyl, and Het-C₀₋₆alkyl;

R¹³ is selected from the group consisting of: H, C₁₋₆alkyl,Ar—C₀₋₆alkyl, and Het-C₀₋₆alkyl;

R′ is selected from the group consisting of: H, C₁₋₆alkyl, Ar—C₀₋₆alkyl,and Het-C₀₋₆alkyl;

R″ is selected from the group consisting of: H, C₁₋₆alkyl, Ar—C₀₋₆alkyl,or Het-C₀₋₆alkyl;

R′″ is selected from the group consisting of:

C₁₋₆alkyl, especially selected from the group consisting of: methyl,ethyl, propyl, butyl, pentyl and hexyl, more especially methyl;

preferably 5-, 6- or 7-C₁₋₆alkyl, especially selected from the groupconsisting of: 5-, 6- or 7-methyl, -ethyl, -propyl, -butyl, -pentyl and-hexyl, more especially 5-, 6- or 7-methyl;

more preferably 6- or 7-C₁₋₆alkyl, especially selected from the groupconsisting of: 6- or 7-methyl, -ethyl, -propyl, -butyl, -pentyl and-hexyl, more especially 6- or 7-methyl;

yet more preferably cis-7-C₁₋₆alkyl as shown in Formula Ia:

wherein R′″ is C₁₋₆alkyl, especially selected from the group consistingof: methyl, ethyl, propyl, butyl, pentyl and hexyl;

most preferably cis-7-methyl, as shown in Formula Ia wherein R′″ ismethyl;

X is selected from the group consisting of: CH₂, S, and 0;

Z is selected from the group consisting of: C(O) and CH₂;

n is an integer from 1 to 5;

and pharmaceutically acceptable salts, hydrates and solvates thereof.

The following compounds are preferred novel intermediates:

-   3-methyl-1-(pyridine-2-sulfonyl)-2,3,4,7-tetrahydro-1H-azepine;-   5-methyl-3-(pyridine-2-sulfonyl)-8-oxa-3-aza-bicyclo[5.1.0]octane;-   4-azido-5-methyl-1-(pyridine-2-sulfonyl)-azepan-3-ol;-   4-amino-6-methyl-1-(pyridine-2-sulfonyl)-azepan-3-ol;-   {(S)-1-[3-hydroxy-6-methyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-carbamic    acid tert-butyl ester;-   5-methoxy-benzofuran-2-carboxylic acid    {(S)-1-[3-hydroxy-6-methyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl    )-amide;-   allyl-(1-methyl-pent-4-enyl)-carbamic acid benzyl ester;-   2-methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester;-   4-methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acid benzyl    ester;-   5-azido-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester;-   5-amino-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester;-   (2R,5S,6S)-5-((S)-2-tert-butoxycarbonylamino-4-methyl-pentanoylamino)-6-hydroxy-2-methyl-azepane-1-carboxylic    acid benzyl ester;-   (2S,5R,6R)-5-((S)-2-tert-butoxycarbonylamino-4-methyl-pentanoylamino)-6-hydroxy-2-methyl-azepane-1-carboxylic    acid benzyl ester;-   [(S)-1-((3S,4S,7R)-3-hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic    acid tert-butyl ester;-   [(S)-1-((3R,4R,7S)-3-hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic    acid tert-butyl ester;-   [(S)-1-((3S,4S,7R)-1-benzenesulfonyl-3-hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic    acid tert-butyl ester;-   [(S)-1-((3R,4R,7S)-1-benzenesulfonyl-3-hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic    acid tert-butyl ester;-   (S)-2-amino-4-methyl-pentanoic acid    ((3S,4S,7R)-1-(2-pyridine)-sulfonyl-3-hydroxy-7-methyl-azepan-4-yl)-amide;-   (S)-2-amino-4-methyl-pentanoic acid    ((3R,4R,7S)-1-(2-pyridine)-sulfonyl-3-hydroxy-7-methyl-azepan-4-yl)-amide;-   benzofuran-2-carboxylic acid    {(S)-1-[(3S,4S,7R)-3-hydroxy-7-methyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;-   benzofuran-2-carboxylic acid    {(S)-1-[(3R,4R,7S)-3-hydroxy-7-methyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;-   ((R)-1-methyl-pent-4-enyl)-carbamic acid benzyl ester;-   allyl-((R)-1-methyl-pent-4-enyl)-carbamic acid benzyl ester;-   2-methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester;-   (1S,4R,7R)-4-methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic    acid benzyl ester;-   (2R,5S,6S)-5-azido-6-hydroxy-2-methyl-azepane-1-carboxylic acid    benzyl ester;-   (2R,5S,6S)-5-amino-6-hydroxy-2-methyl-azepane-1-carboxylic acid    benzyl ester;-   (2R,5S,6S)-5-((S)-2-tert-butoxycarbonylamino-4-methyl-pentanoylamino)-6-hydroxy-2-methyl-azepane-1-carboxylic    acid benzyl ester;-   [(S)-1-((3S,4S,7R)-3-hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic    acid tert-butyl ester;-   [(S)-1-((3S,4S,7R)-2-pyridinesulfonyl-3-hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic    acid tert-butyl ester;-   (S)-2-amino-4-methyl-pentanoic acid    ((3S,4S,7R)-1-(2-pyridine)-sulfonyl-3-hydroxy-7-methyl-azepan-4-yl)-amide;-   5-methoxy-benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[(3R,4R,6R)-6-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;-   benzo[b]thiophene-2-carboxylic acid    {(S)-1-[(3S,4S,6S)-6-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;-   benzo[b]thiophene-2-carboxylic acid    {(S)-1-[(3R,4R,6R)-6-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;-   3-methyl-benzofuran-2-carboxylic acid    {(S)-1-[(3S,4S,6S)-6-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;-   3-methyl-benzofuran-2-carboxylic acid    {(S)-1-[(3R,4R,6R)-6-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;-   thieno[3,2-b]thiophene-2-carboxylic acid    {(S)-1-[(3S,4S,6S)-6-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;-   thieno[3,2-b]thiophene-2-carboxylic acid    {(S)-1-[(3S,4R,6R)-6-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;-   benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[(3S,4S,7R)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;-   benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[(3S,4S,7S)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;-   benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[(3R,4R,7S)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;-   benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[(3R,4R,7R)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;-   ((R)-2-iodo-1-methyl-ethyl)-carbamic acid benzyl ester-   ((R)-1-methyl-pent-4-enyl)-carbamic acid benzyl ester;-   allyl-((R)-1-methyl-pent-4-enyl)-carbamic acid benzyl ester;-   2-methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester;-   (1S,4R,7R)-4-methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic    acid benzyl ester;-   (2R,5S,6S)-5-azido-6-hydroxy-2-methyl-azepane-1-carboxylic acid    benzyl ester;-   (2R,5S,6S)-5-amino-6-hydroxy-2-methyl-azepane-1-carboxylic acid    benzyl ester;-   (2R,5S,6S)-5-((S)-2-tert-butoxycarbonylamino-4-methyl-pentanoylamino)-6-hydroxy-2-methyl-azepane-1-carboxylic    acid benzyl ester;-   [(S)-1-((3S,4S,7R)-3-hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic    acid tert-butyl ester;-   [(S)-1-((3S,4S,7R)-2-pyridinesulfonyl-3-hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic    acid tert-butyl ester;-   (S)-2-amino-4-methyl-pentanoic acid    ((3S,4S,7R)-1-(2-pyridine)-sulfonyl-3-hydroxy-7-methyl-azepan-4-yl)-amide;-   furo[3,2-b]pyridine-2-carboxylic acid    {(S)-1-[(3S,4S,7R)-3-hydroxy-7-methyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;-   furo[3,2-b]pyridine-2-carboxylic acid    {(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;-   3-methyl-furo[3,2-b]pyridine-2-carboxylic acid    {(S)-1-[(3S,4S,7R)-3-hydroxy-7-methyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;-   3-methyl-furo[3,2-b]pyridine-2-carboxylic acid    {(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;-   quinoline-6-carboxylic acid    {(S)-3-methyl-1-[(3S,4S,7R)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;-   quinoline-3-carboxylic acid    {(S)-3-methyl-1-[(3S,4S,7R)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;-   5-methoxy-benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[(3S,4S,7R)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;-   3-methyl-benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[(3S,4S,7R)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;-   thieno[3,2-b]thiophene-2-carboxylic acid    {(S)-3-methyl-1-[(3S,4S,7R)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;-   quinoxaline-2-carboxylic acid    {(S)-3-methyl-1-[(3S,4S,7R)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;-   thieno[3,2-b]thiophene-2-carboxylic acid    {(S)-3-methyl-1-[(3S,4S,7R)-7-methyl-3-hydroxy-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;-   3-methyl-benzofuran-2-carboxylicacid    {(S)-3-methyl-1-[(3S,4S,7R)-7-methyl-3-hydroxy-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;-   benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[(3S,4S,7R)-7-methyl-3-hydroxy-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;-   quinoline-2-carboxylic acid    {(S)-3-methyl-1-[(3S,4S,7R)-7-methyl-3-hydroxy-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;-   5,6-difluoro-benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[(3S,4S,7R)-7-methyl-3-hydroxy-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;-   5-fluoro-3-methyl-benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[(3S,4S,7R)-7-methyl-3-hydroxy-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-butyl}-amide;-   5-fluoro-benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[(3S,4S,7R)-7-methyl-3-hydroxy-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;-   3-methyl-furo[3,2-b]]pyridine-2-carboxylic acid    {(S)-3-methyl-1-[(3S,4S,7R)-7-methyl-3-hydroxy-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;-   cyclohexanecarboxylic acid    {(S)-3-methyl-1-[(3S,4S,7R)-7-methyl-3-hydroxy-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;-   (S)-2-(2-cyclohexyl-ethanoylamino)-4-methyl-pentanoic acid    [(3S,4S,7R)-7-methyl-3-hydroxy-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-yl]-amide;-   (S)-2-(3-cyclohexyl-propanoylamino)-4-methyl-pentanoic acid    [(3S,4S,7R)-7-methyl-3-hydroxy-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-yl]-amide;-   (S)-2-(4-cyclohexyl-butanoylamino)-4-methyl-pentanoic acid    [(3S,4S,7R)-7-methyl-3-hydroxy-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-yl]-amide;-   (S)-2-(5-cyclohexyl-pentanoylamino)-4-methyl-pentanoic acid    [(3S,4S,7R)-7-methyl-3-hydroxy-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-yl]-amide;-   benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[(3S,4S,7R)-7-methyl-3-hydroxy-1-(5-trifluoromethyl-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;-   5-fluoro-benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[(3S,4S,7R)-7-methyl-3-hydroxy-1-(5-trifluoromethyl-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;-   thieno[3,2-b]thiophene-2-carboxylic acid    {(S)-3-methyl-1-[(3S,4S,7R)-7-methyl-3-hydroxy-1-(5-trifluoromethyl-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;-   benzofuran-2-carboxylic acid    {1-[(3S,4S,7R)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-cyclohexyl}-amide;-   thiophene-3-carboxylic acid    {(S)-3,3-dimethyl-1-[(3S,4S,7R)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;-   furan-2-carboxylic acid    {(S)-3,3-dimethyl-1-[(3S,4S,7R)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;-   thieno[3,2-b]thiophene-2-carboxylic acid    {(S)-3,3-dimethyl-1-[(3S,4S,7R)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;-   benzofuran-2-carboxylic acid    {(S)-2-cyclohexyl-1-[(3S,4S,7R)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;-   furan-2-carboxylic acid    {(S)-2-cyclohexyl-1-[(3S,4S,7R)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;-   thiophene-3-carboxylic acid    {(S)-2-cyclohexyl-1-[(3S,4S,7R)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;-   3-methyl-furo[3,2-b]-pyridine-2-carboxylic acid    {(S)-2-cyclohexyl-1-[(3S,4S,7R)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;-   (2R,4aR,8aR)-octahydro-benzo[1,4]dioxine-2-carboxylic acid    [(S)-1-((3S,4S,7R)-1-methanesulfonyl-7-methyl-3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide;-   furan-2-carboxylic acid    [(S)-2-cyclohexyl-1-((3S,4S,7R)-7-methyl-3-hydroxy-1-propyl-azepan-4-ylcarbamoyl)-ethyl]-amide;-   thiophene-3-carboxylic acid    [(S)-2-cyclohexyl-1-((3S,4S,7R)-7-methyl-3-hydroxy-1-propyl-azepan-4-ylcarbamoyl)-ethyl]-amide;-   benzofuran-2-carboxylic acid    [(S)-2-cyclohexyl-1-((3S,4S,7R)-7-methyl-3-hydroxy-1-propyl-azepan-4-ylcarbamoyl)-ethyl]-amide;-   1-(3-cyclohexyl-propanoylamino)-cyclohexanecarboxylic acid    ((3S,4S,7R)-1-cyclohexylmethyl-7-methyl-3-hydroxy-azepan-4-yl)-amide;-   benzofuran-2-carboxylic acid    [1-((3S,4S,7R)-1-cyclohexylmethyl-7-methyl-3-hydroxy-azepan-4-ylcarbamoyl)-cyclohexyl]-amide;-   benzofuran-2-carboxylic acid    [(S)-3-methyl-1-((3S,4S,7R)-7-methyl-3-hydroxy-1-propyl-azepan-4-ylcarbamoyl)-butyl]-amide;-   (2R,5S)-5-((S)-2-tert-butoxycarbonylamino-4-methyl-pentanoylamino)-2-methyl-6-hydroxy-azepane-1-carboxylic    acid benzyl ester;-   benzofuran-2-carboxylic acid    {(S)-3-methyl-1-[(3S,4S,7R)-7-methyl-1-(1-morpholin-4-yl-methanoyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl)-amide;-   (S)-2-(3-cyclohexyl-propanoylamino)-4-methyl-pentanoic acid    [(3S,4S,7R)-7-methyl-1-(1-morpholin-4-yl-methanoyl)-3-hydroxy-azepan-4-yl]-amide;-   (2R,5S,6S)-5-{(S)-2-[(1-benzofuran-2-yl-methanoyl)-amino]-4-methyl-pentanoylamino}-2-methyl-6-hydroxy-azepane-1-carboxylic    acid (tetrahydro-pyran-4-yl)-amide;-   (S)-2-{[1-((2R,5S,6S)-5-{(S)-2-[(1-benzofuran-2-yl-methanoyl)-amino]-4-methyl-pentanoylamino}-2-methyl-6-hydroxy-azepan-1-yl)-methanoyl]-amino)-4-methyl-pentanoic    acid methyl ester;-   (S)-2-{[1-(4-{(S)-2-[(1-benzofuran-2-yl-methanoyl)-amino]-4-methyl-pentanoylamino}-3-hydroxy-azepan-1-yl)-methanoyl]-amino)-4-methyl-pentanoicacid    methyl ester;-   (S)-4-methyl-2-{[1-((2R,5S,6S)-2-methyl-5-f    (S)-4-methyl-2-[(1-quinolin-8-yl-methanoyl)-amino]-pentanoylamino}-6-hydroxy-azepan-1-yl)-methanoyl]-amino}-pentanoic    acid methyl ester;-   (R)-2-{[1-(4-{(S)-2-[(1-benzofuran-2-yl-methanoyl)-amino]-4-methyl-pentanoylamino}-3-hydroxy-azepan-1-yl)-methanoyl]-amino}-4-methyl-pentanoic    acid methyl ester;-   2-biphenyl-3-yl-4-methyl-pentanoic acid    [(3R,4R,7R)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-yl]-amide;-   3-methyl-furo[3,2-b]-pyridine-2-carboxylic acid    {1-[(4S,7R)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-cyclohexyl}-amide;    and-   1-(3-cyclohexyl-propanoylamino)-cyclohexanecarboxylic acid    [(4S,7R)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-yl]-amide.

Process for Synthesis of Inventive Compounds

Referring to Schemes 1-8 herein above, the present invention provides aprocess for the synthesis of compounds of Formula (I) comprising thestep of oxidizing the appropriate compound of Formula (II) with anoxidant to provide the compound of Formula (I) as a mixture ofdiastereomers. Preferably the oxidant is sulfur trioxide-pyridinecomplex.

Referring to Scheme 4, the present invention also provides a process forthe synthesis of deuterated compounds of Formula (I). Specifically, whena deuterated isomer is desired, an additional step, following theoxidation step, of deuterating the protonated isomer with a deuteratingagent to provide the deuterated compound of Formula (I) as a mixture ofdiastereomers is added to the synthesis. Preferably, the deuteratingagent is CD₃OD:D₂O (10:1) in triethylamine.

The process further comprises the step of separating the diasteromers ofFormula (I) by separating means, preferably by high presssure liquidchromatography (HPLC).

Utility of the Present Invention

The compounds of Formula I are useful as protease inhibitors,particularly as inhibitors of cysteine and serine proteases, moreparticularly as inhibitors of cysteine proteases, even more particularlyas inhibitors of cysteine proteases of the papain superfamily, yet moreparticularly as inhibitors of cysteine proteases of the cathepsinfamily, most particularly as inhibitors of cathepsin K. The presentinvention also provides useful compositions and formulations of saidcompounds, including pharmaceutical compositions and formulations ofsaid compounds.

The present compounds are useful for treating diseases in which cysteineproteases are implicated, including infections by pneumocystis carinii,trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; as wellas in schistosomiasis, malaria, tumor metastasis, metachromaticleukodystrophy, muscular dystrophy, amytrophy; and especially diseasesin which cathepsin K is implicated, most particularly diseases ofexcessive bone or cartilage loss, including osteoporosis, gingivaldisease including gingivitis and periodontitis, arthritis, morespecifically, osteoarthritis and rheumatoid arthritis, Paget's disease;hypercalcemia of malignancy, and metabolic bone disease.

Parasites known to utilize cysteine proteases in their life cycle (andthe diseases caused by these parasites) include Trypanosoma cruzi,Trypanosoma Brucei [trypanosomiasis (African sleeping sickness, Chagasdisease)], Leishmania mexicana, Leishmania pifanoi, Leishmania major(leishmaniasis), Schistosoma mansoni (schistosomiasis), Onchocercavolvulus [onchocerciasis (river blindness)] Brugia pahangi, Entamoebahistolytica, Giardia lambia, the helminths, Haemonchus contortus andFasciola hepatica, as well as helminths of the genera Spirometra,Trichinella, Necator and Ascaris, and protozoa of the generaCryptosporidium, Eimeria, Toxoplasma and Naegleria. The compounds of thepresent invention are suitable for treating diseases caused by theseparasites which may be therapeutically modified by altering the activityof cysteine proteases. In particular, the present compounds are usefulfor treating malaria by inhibiting falcipain.

Metastatic neoplastic cells also typically express high levels ofproteolytic enzymes that degrade the surrounding matrix, and certaintumors and metastatic neoplasias may be effectively treated with thecompounds of this invention.

The present invention also provides methods of treatment of diseasescaused by pathological levels of proteases, particularly cysteine andserine proteases, more particularly cysteine proteases, even moreparticularly cysteine proteases of the papain superfamily, yet moreparticularly cysteine proteases of the cathepsin family, which methodscomprise administering to an animal, particularly a mammal, mostparticularly a human in need thereof a compound of the presentinvention. The present invention especially provides methods oftreatment of diseases caused by pathological levels of cathepsin K,which methods comprise administering to an animal, particularly amammal, most particularly a human in need thereof an inhibitor ofcathepsin K, including a compound of the present invention. The presentinvention particularly provides methods for treating diseases in whichcysteine proteases are implicated, including infections by pneumocystiscarinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata;as well as in schistosomiasis, malaria, tumor metastasis, metachromaticleukodystrophy, muscular dystrophy, amytrophy, and especially diseasesin which cathepsin K is implicated, most particularly diseases ofexcessive bone or cartilage loss, including osteoporosis, gingivaldisease including gingivitis and periodontitis, arthritis, morespecifically, osteoarthritis and rheumatoid arthritis, Paget's disease,hypercalcemia of malignancy, and metabolic bone disease.

The present method provides treatment of diseases (in parentheses)caused by infection by Trypanosoma cruzi, Trypanosoma Brucei[trypanosomiasis (African sleeping sickness, Chagas disease)],Leishmania mexicana, Leishmania pifanoi, Leishmania major(leishmaniasis), Schistosoma mansoni (schistosomiasis), Onchocercavolvulus [onchocerciasis (river blindness)] Brugia pahangi, Entamoebahistolytica, Giardia lambia, the helminths, Haemonchus contortus andFasciola hepatica, as well as helminths of the genera Spirometra,Trichinella, Necator and Ascaris, and protozoa of the generaCryptosporidium, Eimeria, Toxoplasma and Naegleria by inhibitingcysteine proteases of the papain superfamily by administering to apatient in need thereof, particularly an animal, more particularly amammal, most particularly a human being, one or more of the above-listedcompounds.

Most particularly, the present invention provides a method of treatingmalaria, caused by infection with Plasmodium falciparum, by theinhibition of falcipain by administering to a patient in need thereof,particularly an animal, more particularly a mammal, most particularly ahuman being, one or more of the above-listed compounds.

The present method may be practiced by administering the above-listedcompounds alone or in combination, with each other, or with othertherapeutically effective compounds.

This invention further provides a method for treating osteoporosis orinhibiting bone loss which comprises internal administration to apatient of an effective amount of a compound of Formula I, alone or incombination with other inhibitors of bone resorption, such asbisphosphonates (i.e., allendronate), hormone replacement therapy,anti-estrogens, or calcitonin. In addition, treatment with a compound ofthis invention and an anabolic agent, such as bone morphogenic protein,iproflavone, may be used to prevent bone loss or to increase bone mass.

For acute therapy, parenteral administration of a compound of Formula Iis preferred. An intravenous infusion of the compound in 5% dextrose inwater or normal saline, or a similar formulation with suitableexcipients, is most effective, although an intramuscular bolus injectionis also useful. Typically, the parenteral dose will be about 0.01 toabout 100 mg/kg; preferably between 0.1 and 20 mg/kg, in a manner tomaintain the concentration of drug in the plasma at a concentrationeffective to inhibit cathepsin K. The compounds are administered one tofour times daily at a level to achieve a total daily dose of about 0.4to about 400 mg/kg/day. The precise amount of an inventive compoundwhich is therapeutically effective, and the route by which such compoundis best administered, is readily determined by one of ordinary skill inthe art by comparing the blood level of the agent to the concentrationrequired to have a therapeutic effect.

The compounds of this invention may also be administered orally to thepatient, in a manner such that the concentration of drug is sufficientto inhibit bone resorption or to achieve any other therapeuticindication as disclosed herein. Typically, a pharmaceutical compositioncontaining the compound is administered at an oral dose of between about0.1 to about 50 mg/kg in a manner consistent with the condition of thepatient. Preferably the oral dose would be about 0.5 to about 20 mg/kg.

No unacceptable toxicological effects are expected when compounds of thepresent invention are administered in accordance with the presentinvention.

Biological Assays

The compounds of this invention may be tested in one of severalbiological assays to determine the concentration of compound which isrequired to have a given pharmacological effect.

Determination of Cathepsin K Proteolytic Catalytic Activity

All assays for cathepsin K were carried out with human recombinantenzyme. Standard assay conditions for the determination of kineticconstants used a fluorogenic peptide substrate, typicallyCbz-Phe-Arg-AMC, and were determined in 100 mM Na acetate at pH 5.5containing 20 mM cysteine and 5 mM EDTA. Stock substrate solutions wereprepared at concentrations of 10 or 20 mM in DMSO with 20 uM finalsubstrate concentration in the assays. All assays contained 10% DMSO.Independent experiments found that this level of DMSO had no effect onenzyme activity or kinetic constants. All assays were conducted atambient temperature. Product fluorescence (excitation at 360 nM;emission at 460 nM) was monitored with a Perceptive Biosystems CytofluorII fluorescent plate reader. Product progress curves were generated over20 to 30 minutes following formation of AMC product.

Inhibition Studies

Potential inhibitors were evaluated using the progress curve method.Assays were carried out in the presence of variable concentrations oftest compound. Reactions were initiated by addition of enzyme tobuffered solutions of inhibitor and substrate. Data analysis wasconducted according to one of two procedures depending on the appearanceof the progress curves in the presence of inhibitors. For thosecompounds whose progress curves were linear, apparent inhibitionconstants (K_(i,app)) were calculated according to equation 1 (Brandt etal., Biochemitsry, 1989, 28, 140):v=V _(m) A/[K _(a)(1+1/K _(i,app))+A]  (1)where v is the velocity of the reaction with maximal velocity V_(m), Ais the concentration of substrate with Michaelis constant of K_(α), andI is the concentration of inhibitor.

For those compounds whose progress curves showed downward curvaturecharacteristic of time-dependent inhibition, the data from individualsets was analyzed to give k_(obs) according to equation 2:[AMC]=v _(ss) t+(v ₀ −v _(ss))[1−exp(−k _(obs) t)]/k _(obs)  (2)where [AMC] is the concentration of product formed over time t, v₀ isthe initial reaction velocity and v_(ss) is the final steady state rate.Values for k_(obs) were then analyzed as a linear function of inhibitorconcentration to generate an apparent second order rate constant(k_(obs)/inhibitor concentration or k_(obs)/[I]) describing thetime-dependent inhibition. A complete discussion of this kinetictreatment has been fully described (Morrison et al., Adv. Enzymol.Relat. Areas Mol. Biol., 1988, 61, 201).Human Osteoclast Resorption Assay

Aliquots of osteoclastoma-derived cell suspensions were removed fromliquid nitrogen storage, warmed rapidly at 37° C. and washed ×1 inRPMI-1640 medium by centrifugation (1000 rpm, 5 min at 4° C.). Themedium was aspirated and replaced with murine anti-HLA-DR antibody,diluted 1:3 in RPMI-1640 medium, and incubated for 30 min on ice Thecell suspension was mixed frequently.

The cells were washed ×2 with cold RPMI-1640 by centrifugation (1000rpm, 5 min at 4° C.) and then transferred to a sterile 15 mL centrifugetube. The number of mononuclear cells were enumerated in an improvedNeubauer counting chamber.

Sufficient magnetic beads (5/mononuclear cell), coated with goatanti-mouse IgG, were removed from their stock bottle and placed into 5mL of fresh medium (this washes away the toxic azide preservative). Themedium was removed by immobilizing the beads on a magnet and is replacedwith fresh medium.

The beads were mixed with the cells and the suspension was incubated for30 min on ice. The suspension was mixed frequently. The bead-coatedcells were immobilized on a magnet and the remaining cells(osteoclast-rich fraction) were decanted into a sterile 50 mL centrifugetube. Fresh medium was added to the bead-coated cells to dislodge anytrapped osteoclasts. This wash process was repeated ×10. The bead-coatedcells were discarded.

The osteoclasts were enumerated in a counting chamber, using alarge-bore disposable plastic pasteur pipette to charge the chamber withthe sample. The cells were pelleted by centrifugation and the density ofosteoclasts adjusted to 1.5×10⁴/mL in EMEM medium, supplemented with 10%fetal calf serum and 1.7 g/litre of sodium bicarbonate. 3 mL aliquots ofthe cell suspension (per treatment) were decanted into 15 mL centrifugetubes. These cells were pelleted by centrifugation. To each tube 3 mL ofthe appropriate treatment was added (diluted to 50 uM in the EMEMmedium). Also included were appropriate vehicle controls, a positivecontrol (87MEM1 diluted to 100 ug/mL) and an isotype control (IgG2adiluted to 100 ug/mL). The tubes were incubate at 37° C. for 30 min.

0.5 mL aliquots of the cells were seeded onto sterile dentine slices ina 48-well plate and incubated at 37° C. for 2 h. Each treatment wasscreened in quadruplicate. The slices were washed in six changes of warmPBS (10 mL/well in a 6-well plate) and then placed into fresh treatmentor control and incubated at 37° C. for 48 h. The slices were then washedin phosphate buffered saline and fixed in 2% glutaraldehyde (in 0.2Msodium cacodylate) for 5 min., following which they were washed in waterand incubated in buffer for 5 min at 37° C. The slices were then washedin cold water and incubated in cold acetate buffer/fast red garnet for 5min at 4° C. Excess buffer was aspirated, and the slices were air driedfollowing a wash in water.

The TRAP positive osteoclasts were enumerated by bright-field microscopyand were then removed from the surface of the dentine by sonication. Pitvolumes were determined using the Nikon/Lasertec ILM21W confocalmicroscope.

General

Nuclear magnetic resonance spectra were recorded at either 250 or 400MHz using, respectively, a Bruker AM 250 or Bruker AC 400 spectrometer.CDCl₃ is deuteriochloroform, DMSO-d₆ is hexadeuteriodimethylsulfoxide,and CD₃OD is tetradeuteriomethanol. Chemical shifts are reported inparts per million (d) downfield from the internal standardtetramethylsilane. Abbreviations for NMR data are as follows: s=singlet,d=doublet, t=triplet, q=quartet, m=multiplet, dd=doublet of doublets,dt=doublet of triplets, app=apparent, br=broad. J indicates the NMRcoupling constant measured in Hertz. Continuous wave infrared (1R)spectra were recorded on a Perkin-Elmer 683 infrared spectrometer, andFourier transform infrared (FTIR) spectra were recorded on a NicoletImpact 400 D infrared spectrometer. IR and FTIR spectra were recorded intransmission mode, and band positions are reported in inversewavenumbers (cm⁻¹). Mass spectra were taken on either VG 70 FE, PE SyxAPI III, or VG ZAB HF instruments, using fast atom bombardment (FAB) orelectrospray (ES) ionization techniques. Elemental analyses wereobtained using a Perkin-Elmer 240 C elemental analyzer. Melting pointswere taken on a Thomas-Hoover melting point apparatus and areuncorrected. All temperatures are reported in degrees Celsius.

Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin layerplates were used for thin layer chromatography. Both flash and gravitychromatography were carried out on E. Merck Kieselgel 60 (230400 mesh)silica gel.

Where indicated, certain of the materials were purchased from theAldrich Chemical Co., Milwaukee, Wis., Chemical Dynamics Corp., SouthPlainfield, N.J., and Advanced Chemtech, Louisville, Ky.

EXAMPLES

In the following synthetic examples, temperature is in degreesCentigrade (° C.). Unless otherwise indicated, all of the startingmaterials were obtained from commercial sources. Without furtherelaboration, it is believed that one skilled in the art can, using thepreceding description, utilize the present invention to its fullestextent. These Examples are given to illustrate the invention, not tolimit its scope. Reference is made to the claims for what is reserved tothe inventors hereunder.

Example 1 5-Methoxy-benzofuran-2-carboxylic acid{(S)-3-methyl-1-[(4S,6S)-6-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

5-Methoxy-benzofuran-2-carboxylic acid{(S)-3-methyl-1-[(4R,6R)-6-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

a. Allyl-(2-methyl-pent-4-enyl)-amine

To a solution of 2-methyl-pent-4-enoic acid ethyl ester (7.1 g, 50 mmol)was added dropwise a solution of DIBAL (1.0 M in hexanes, 75 ml) at −78C over 1.0 h. After the addition, the reaction mixture was stirred at−78 C for another hour. The reaction was quenched with saturated NH4Cl(10 ml) and 4% HCl, then was extracted with EtOAc (3×100 ml). Thecombined organic extracts were dried with MgSO₄, filtered, concentratedby rotary evaporation and the crude reaction product was used in thenext reaction without further purification. 2-Methyl-4-pentenal (3.3 g,33.7 mmol) was dissolved in CH₂Cl₂ (100 ml). To this solution allylamine(2.9 g, 50.5 mmol) was added. Molecular sieves (5 g) were used to absorbwater generated during the reaction. The mixture was stirred at roomtemperature over night. The reaction mixture was concentrated by rotaryevaporation and the crude product was used in the next reaction withoutfurther purification. Allyl-(2-methyl-pent-4-enylidene)-amine (3.2 g,23.4 mmol) was diluted in 50 ml MeOH. To the solution NaBH₄ (1.0 g, 26.3mmol) was added at 0° C. After addition the mixture was stirred at RTfor 5 h. The reaction mixture was concentrated and the residue waspartitioned between EtOAc/20% aq. NaOH. The organic layer was dried overNa₂SO₄, fitered and concentrated by rotary evaporation to giveallyl-(2-methyl-pent-4-enyl)-amine (1.5 g 48% yield): 1H-NMR (400 Hz,CDCl3): d=5.93-5.68 (m, 2H), 5.18-4.92(m, 4H), 3.21(d, 2H), 2.60-2.40(m,2H), 1.97-1.65(m, 2H), 0.92(d, 3H)

b. Pyridine-2-sulfonic acid allyl-(2-methyl-pent-4-enyl)-amide

Allyl-(2-methyl-pent-4-enyl)-amine (1.0 g, 7.2 mmol) and NMM (1.7 g,17.2 mmol) were mixed in 30 ml CH₂Cl₂.2-pyridinesulphonyl chloride (1.53g, 8.6 mmol) was added slowly to the solution while it was cooled in anice-water bath. After addition, the reaction mixture was stirred at RTovernight. The reaction mixture was washed with 10% NaHCO₃ and thebrine, then was purified by column chromatography to give the titlecompound as a colorless oil (1.2 g, 60% yield): MS (M+H+) 281.2; 1H-NMR(400 Hz, CDCl3): d=8.70(d, 1H), 8.0-7.75(m, 2H), 7.5 (m, 1H)5.80-5.60(m, 2H), 5.15-4.92(m, 4H), 4.00-3.90(m, 2H), 3.20-3.06(m, 2H),2.15(m, 1H), 1.85(m, 2H), 0.89(d, 3H)

c. 3-methyl-1-(pyridine-2-sulfonyl)-2,3,4,7-tetrahydro-1H-azepine

Pyridine-2-sulfonic acid allyl-(2-methyl-pent-4-enyl)-amide (1.2 g, 4.3mmol) was diluted in CH₂Cl₂ (100 ml). After carefully degass by Ar,Grubbs catalyst (0.35 g, 0.43 mmol) was added under Ar protection. Themixture was then refluxed for 2 h before the reaction mixture wasconcentrated by rotary evaporation. The product was purified by columnchromatography (5%-20% EtOAc/hexanes) to give the title compound (0.9 g,83% yield): MS (M+H+):253.2; 1H-NMR (400 Hz, CDCl3): d=8.70(d, 1H),8.0-7.75(m, 2H), 7.5 (m, 1H) 5.79-5.60(m, 2H), 4.00(d, 2H), 3.65(dd,1H), 3.22(dd, 1H), 2.30-2.05(m, 3H), 0.96(d, 3H)

d. 5-methyl-3-(pyridine-2-sulfonyl)-8-oxa-3-aza-bicyclo[5.1.0]octane

To the solution of3-methyl-1-(pyridine-2-sulfonyl)-2,3,4,7-tetrahydro-1H-azepine (1.3 g,5.16 mmol) in CH₂Cl₂ (50 ml) was added NaHCO₃ (1.3 g, 15.5 mmol) andthen mCPBA (2.67 g, 15.5 mmol) in portions. Stirred at RT for 4 h beforeworked up by washing with 15% NaOH, saturated K₂CO₃ and brine. Driedover Na₂SO₄. The reaction mixture was concentrated by rotary evaporationand two insomers were seperated on column chromatography (30%-40%EtoAc/Hexane). The first elution (trans-isomer, 230 mg) was used in nextsteps, the second elution (cis-insomer 200 mg) was saved: MS (M+H+):269.0; 1H-NMR (400 Hz, CDCl3): d=8.70(d, 1H), 8.0-7.75(m, 2H), 7.50 (m,1H) 4.39(m, 1H), 3.92(m, 1H), 3.34-2.00(m, 6H), 1.40(m, 1H), 0.88(d, 3H)

e. 4-Azido-5-methyl-1-(pyridine-2-sulfonyl)-azepan-3-ol

5-methyl-3-(pyridine-2-sulfonyl)-8-oxa-3-aza-bicyclo[5.1.0]octane (230mg, 0.86 mmol) was dissolved in the mixture of 8 ml MeOH and 2 ml H₂O.NaN₃ (170 mg, 2.6 mmol) and NH₄Cl (140 mg, 2.6 mmol) were added to thesolution. The resulting mixture was refluxed overnight. After theremoval of MeOH, the residue was diluted in EtOAc and washed with 10%NaHCO₃ and brine. Purified on column chromatography gave the titlecompound (170 mg, yield 64%). MS (M+H+) 312.2; 1H-NMR (400 Hz, CDCl3):d=8.69(d, 1H), 8.04-7.94(m, 2H), 7.54 (m, 1H) 4.00-2.95 (m, 7H), 2.20(m,1H), 1.90-1.74(m, 2H), 0.98(d, 3H)

f. 4-Amino-6-methyl-1-(pyridine-2-sulfonyl)-azepan-3-ol

4-Azido-6-methyl-1-(pyridine-2-sulfonyl)-azepan-3-ol (0.33 g, 1.06 mmol)was dissolved in THF (50 ml) and H₂O (0.2 ml). PPh₃ (0.42 g, 1.59 mmol)was added to this solution. The reaction mixture was stirred at 45° C.over night. TLC showed no starting material left. THF was evaperated,azeotroped by toluene (2×100 ml). The resulting thick oil was dissolvedin MeOH, treated with HCl in ether to adjust pH to acidic. More etherwas added and the solution turned cloudy to give the title compound as awhite precipitate (0.21 g, 71% yield) MS (M+H+) 286.0; 1H-NMR (400 Hz,CD3OD): d (ppm): 8.72(d, 1H), 8.14-7.99(m, 2H), 7.68(m, 1H),3.85-3.69(m, 2H), 3.38-3.22(m, 3H), 3.10-3.04(m, 2H), 2.04(m, 1H),1.82-1.66(m, 2H), 1.02(d, 3H)

g.{(S)-1-[3-Hydroxy-6-methyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-carbamicacid tert-butyl ester

4-Amino-6-methyl-1-(pyridine-2-sulfonyl)-azepan-3-ol HCl salt (0.21 g,0.59 mmol) was dissolved in 5 ml DMF. To this solution, was addedBoc-Leu-OH (0.22 g, 0.88 mmol) and HBTU (0.34 g, 0.90 mmol) and then NMM(0.24 g, 2.4 mmol). The mixture was stirred at RT overnight. DMF wasremoved under high vacuum. The residue was diluted in EtOAc and washedwith H₂O, 10% NaHCO₃ and brine. Purification by column chromatographygave the title compound (0.2 g, 68% yield). MS (M+H+): 499.1; 1H-NMR(400 Hz, CDCl3): 8.75(d, 1H), 8.0-7.75(m, 2H), 7.5 5(m, 1H) 5.10(m, 1H),4.15-2.90(m, 10H), 2.10-1.48(m, 14H), 1.00(m, 9H)

h. 5-Methoxy-benzofuran-2-carboxylic acid{(S)-1-[3-hydroxy-6-methyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide

To{(S)-1-[3-hydroxy-6-methyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-carbamicacid tert-butyl ester (0.13 g, 0.28 mmol) was added HCl/dioxane (4M, 2.8ml, 11.2 mmol). The mixture was stirred at RT for 2 h before solventsand excess amount of HCl was removed on rotavapor. The result whitesolid was dissolved in 5 ml DMF. To the solution was added5-methoxy-benzofuran-2-carboxylic acid (63.4 mg, 0.33 mmol), HBTU (125g, 0.33 mmol) and NMM (0.14 g, 1.34 mmol). The mixture was stirred at RTovernight. DMF was then removed and the residue was re-dissolved inEtOAc (50 ml), washed with 10% NaHCO₃ (50 ml×2) and brine (50 ml). Thecombined organics were concentrated by rotary evaporation. Purificationby column chromatograghy gave the title compound (110 mg in 69% yield, 2steps): MS (M+H+):573.4; 1H-NMR (400 Hz, CDCl3): d=8.74-8.66(dd, 1H),7.96-6.97(m, 9H), 4.72(m, 1H), 4.18-3.21(m, 7H), 2.81(m, 1H),2.04-1.74(m, 6H), 1.25(m, 2H), 0.99-0.87(m, 9H)

i. 5-Methoxy-benzofuran-2-carboxylic acid{(S)-3-methyl-1-[(4S,6S)-6-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amideand 5-methoxy-benzofuran-2-carboxylic acid{(S)-3-methyl-1-[(4R,6R)-6-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

To a solution of 5-methoxy-benzofuran-2-carboxylic acid{(S)-1-[3-hydroxy-6-methyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide(110 mg, 0.19 mmol) in 5 ml CH₂Cl₂, was added Dess-Martin reagent (122mg, 0.29 mmol) at RT. The solution was stirred for 2 h when 50 ml CH₂Cl₂was added and then washed with 10% NaHCO₃ and brine. Purification bycolumn chromatograghy (50% ethyl acetate in hexane) gave the titlecompound (90 mg, 82% yield). 1H-NMR (400 Hz, CDCl3): d (ppm): 8.69(d,1H), 7.94(m, 2H), 7.39-7.24(m, 3H), 7.02(m, 4H), 5.26(m, 1H), 4.69(m,2H), 3.84(m, 4H), 3.00(m, 1H), 2.05(m, 1H), 1.73(m, 2H), 1.61(m, 4H),1.18(d, 3H), 0.97(d,6H);). The diastereomers were separated by HPLC.Diastereomer 1: MS (M+H+): 571.2; Diastereomer 2: MS (M+H+): 571.2

Example 2 Benzo[b]thiophene-2-carboxylic acid{(S)-1-[(4S,6S)-6-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide

benzo[b]thiophene-2-carboxylic acid{(S)-1-[(4R,6R)-6-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide

Following the procedure of Example 1 (a-i), except substituting“benzo[b]thiophene-2-carboxylic acid” for“5-methoxy-benzofuran-2-carboxylic acid” gave the title compound: MS(M+H+); 1H-NMR (400 Hz, CDCl3): d (ppm): 8.69(d, 1H), 7.97-7.78(m, 5H),7.41-7.39(m, 3H), 6.95(d, 1H), 6.65(d, 1H), 5.25(m, 1H), 4.71-4.60(m,2H), 3.86(d, 1H), 3.80(m, 1H), 2.98(d, 1H), 2.05(m, 2H), 1.75-1.55(m,4H), 1.18(d, 3H), 0.97(d, 6H); The diastereomers were separated by HPLC.Diastereomer 1: MS (M+H+): 557.2; Diastereomer 2: MS (M+H+): 557.2

Example 3 3-Methyl-benzofuran-2-carboxylic acid{(S)-1-[(4S,6S)-6-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide

; and3-methyl-benzofuran-2-carboxylic acid{(S)-1-[(4R,6R)-6-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide

Following the procedure of Example 1 (a-i), except substituting“3-methyl-benzofuran-2-carboxylic acid” for“5-methoxy-benzofuran-2-carboxylic acid” gave the title compound: MS(M+H+) 555.2; 1H-NMR (400 Hz, CDCl3): d (ppm): 8.68(d, 1H), 7.93(m, 2H),7.59-7.27(m, 5H), 7.03-6.96(dd, 2H), 5.26(m, 1H), 4.70-4.61(m, 1H),3.82(d, 1H), 3.76(m, 1H), 2.99(d, 1H), 2.60(s, 3H), 2.05(m, 2H),1.76-1.58(m, 5H), 1.19(d, 3H), 0.97(d, 6H); The diastereomers wereseparated by HPLC. Diastereomer 1: MS (M+H+): 555.2; Diastereomer 2: MS(M+H+): 555.4

Example 4 Thieno[3,2-b]thiophene-2-carboxylic acid((S)-1-[(4S,6S)-6-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide

thieno[3,2-b]thiophene-2-carboxylic acid{(S)-1-[(4R,6R)-6-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide

Following the procedure of Example 1 (a-i), except substituting“thieno[3,2-b]thiophene-2-carboxylic acid” for“5-methoxy-benzofuran-2-carboxylic acid “gave the title compound: MS(M+H+) 563.2; 1H-NMR (400 Hz, CDCl3): d (ppm): 8.69(d, 1H), 7.97-7.78(m,5H), 7.41-7.38(m, 3H), 6.95(d, 1H), 6.65(d, 1H), 5.26(m, 1H),4.69-4.60(m, 2H), 3.85(d, 1H), 3.80(m, 1H), 2.99(d, 1H), 2.04(m, 2H),1.75-1.55(m, 4H), 1.18(d, 3H), 0.97(d, 6H); The diastereomers wereseparated by HPLC. Diastereomer 1: MS (M+H+): 563.2; Diastereomer 2:

MS (M+H+): 563.2

Example 5 Benzofuran-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

benzofuran-2-carboxylic acid{(S)-3-methyl-1-[(4R,7S)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

a. Allyl-(1-methyl-pent-4-enylidene)-amineAllyl-(1-methyl-pent-4-enyl)-amine

Hex-5-en-2-one (9.8 g, 11.6 ml, 100 mmol) was added to a stirredsolution of allylamine (8.55 mmol, 11.25 ml, 150 mmol), 4 Angstrommolecular sieves (52 g), and p-toluene sulfonic acid (10 mg) in CH₂Cl₂(200 ml) and was stirred overnight. The reaction mixture wasconcentrated in vacuo by rotary evaporation and was used in the nextreaction without further purification (13 g, 95%). Electrospray massspec: M+H⁺=137.9

b. Racemic Allyl-(1-methyl-pent-4-enyl)-amine

Sodium borohydride (2.7 g, 71 mmol) was added portionwise to a stirredsolution of allyl-(1-methyl-pent-4-enylidene)-amine (6.5 g, 47 mmol) inMeOH (100 ml) at 0 C. The reaction mixture was stirred for 30 minutes,then warmed to RT. Approximately 90 ml of MeOH was removed from thereaction mixture by rotary evaporation, then the reaction mixture wasdiluted with ether (200 ml), then extracted with water then brine. Thecombined organics were dried with MgSO₄, filtered, concentrated in vacuoby rotary evaporation to give a pale yellow liquid that was used in thenext reaction without further purification (5.2 g, 80%).

c. Racemic Allyl-(1-methyl-pent-4-enyl)-carbamic acid benzyl ester

Carbobenzyloxy chloride (9.56 g, 8 ml) was added dropwise to a stirredsolution of allyl-(1-methyl-pent-4-enyl)-amine (7 g, 50 mmol),triethylamine (5.5 g, 8.0 ml, 57.5 mmol) in CH₂Cl₂ (100 ml) at 0 C. Thereaction mixture was warmed to RT, then was stirred for 2 h. Thereaction mixture was diluted with CH₂Cl₂ (100 ml), then was extractedwith water, then brine. The combined organics were dried with MgSO₄,filtered, concentrated in vacuo by rotary evaporation, then waschromatographed (silica gel, 4% EtOAc/hexanes) to give the titlecompound (8.9 g, 65% yield): Liquid Chromatgraphy/Electrospray massspec: M+H⁺=274.2

d. Racemic 2-Methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzylester

Allyl-(1-methyl-pent-4-enyl)-carbamic acid benzyl ester (1.036 g, 3.8mmol) was dissolved in CH₂Cl₂ (10 ml) and a stream of argon gas wasbubbled into the reaction mixture for 10 minutes. Thenbis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride (StremChemicals, Grubbs' catalyst, 22 mg, 0.027 mmol) was added and thereaction mixture was refluxed for 2 h. Additionalbis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride (11 mg,0.014 mmol) was added and the reaction mixtrue was refluxed for anadditional 1.5 hours. The reaction was cooled to RT under argonovernight, then was concentrated in vacuo by rotary evaporation, thenwas chromatographed (silica gel, 5% EtOAc/hexanes) to give the titlecompound (0.83 g, 89%): 1H NMR: 7.35-7.20 (m, 5H), 5.65 (1H, m), 5.13(2H, AB), 4.45-4.05 (m, 2H), 3.56 (1H, d), 2.25-2.10 (m, 2H), 1.90-1.60(m, 2H), 1.12 (3H, d); Liquid Chromatgraphy/Electrospray mass spec:M+H⁺=246.2.

e. Racemic(1S,4R,7R)-4-Methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acidbenzyl ester

m-Chloro-perbenzoic acid (1.05 g, 57-86% pure) was added to a solutionof 2-methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester(0.83 g, 3.34 mmol) in CH₂Cl₂ at 0 degrees C. The reaction mixture wasstirred for half an hour, then was warmed to RT. Additionalm-chloro-perbenzoic acid (0.3 g, 57-86% pure) was added and the reactionwas stirred 2 h. The reaction mixture was concentrated in vacuo byrotary evaporation, then 80 ml of 9:1 hexanes/EtOAc was added and thereaction mixture was filtered. The filtrate was concentrated in vacuo byrotary evaporation, then was chromatographed (silica gel, 20%EtOAc:hexanes) to give racemic(1S,4R,7S)-4-methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acidbenzyl ester (0.44 g, 50%) and the title compound as a racemic mixtureof the title compound (0.15 g, 17% yield): 1H NMR: 7.42-7.22 (m, 5H),5.13 (2H, s), 4.50-4.15 (m, 2H), 3.27 (1H, d), 3.12-2.95 (1H, m),2.15-1.70 (m, 2H), 1.47 (m, 2H), 1.12 (3H, d); LiquidChromatgraphy/Electrospray mass spec: M+H⁺=262.0.

f. Racemic (2R,5S,6S)-5-Azido-6-hydroxy-2-methyl-azepane-1-carboxylicacid benzyl ester

Sodium azide (0.56 g, 8.62 mmol) was added to a solution of racemic(1S,4R,7R)-4-methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acidbenzyl ester (0.75 g, 2.87 mmol) and ammonium chloride (0.46 g, 8.62mmol) in MeOH (5 ml) and H₂O (0.5 ml), then was refluxed for 6 h. Thereaction mixture was concentrated in vacuo by rotary evaporation, thenwas diluted with water (5 ml) and extracted with EtOAc (10 ml). Theorganic layer was then extracted with water, brine, dried with MgSO₄,filtered, concentrated in vacuo by rotary evaporation, andchromatographed (silica gel, 20% EtOAc/hexanes) to yield the titlecompound (0.7 g, 80%): 7.39-7.30 (m, 5H), 5.15 (2H, s), 4.10-3.67 (m,2H), 3.10 (1H, d), 1.85-1.53 (m, 4H), 1.09 (3H, d); LiquidChromatgraphy/Electrospray mass spec: M+H⁺=305.2.

g. Racemic (2R,5S,6S)-5-Amino-6-hydroxy-2-methyl-azepane-1-carboxylicacid benzyl ester

Triphenylphosphine (1.94 g, 7.4 mmol) was added to a solution of racemic(2R,5S,6S)-5-azido-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzylester (1.5 g, 4.93 mmol) in THF (185 ml) and H₂O (0.7 ml), then washeated to 45 degrees C. overnight. The reaction mixture was then dilutedwith toluene (100 ml×2) and was azeotroped in vacuo by rotaryevaporation twice. The resxulting oil was dissolved in MeOH and HCl inEt₂O and the resulting salt was collected following filtration and wasused in the next reaction without further purification (1.4 g, 90%).

h.(2R,5S,6S)-5-((S)-2-tert-Butoxycarbonylamino-4-methyl-pentanoylamino)-6-hydroxy-2-methyl-azepane-1-carboxylicacid benzyl ester and(2S,5R,6R)-5-((S)-2-tert-Butoxycarbonylamino-4-methyl-pentanoylamino)-6-hydroxy-2-methyl-azepane-1-carboxylicacid benzyl ester

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (0.33 g, 1.73 mmol) wasadded to a solution of Boc-leucine-hydrate (0.43 g, 1.7 mmol),diisopropylethylamine (0.22 g, 0.3 ml, 1.7 mmol), hydroxybenztriazole(0.25 g, 1.85 mmol), and racemic(2R,5S,6S)-5-Amino-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzylester (0.5 g, 1.6 mmol) in DMF (10 ml). The reaction was stirredovernight at RT, then was diluted with EtOAc (100 ml), washed with H₂O(3×50 ml), brine (50 ml), dried with magnesium sulfate, filtered,concentrated in vacuo by rotary evaporation, and chromatographed (silicagel, 50% EtOAc/hexanes) to yield the title compound (0.78 g, 100%): 1HNMR: 7.40-7.29 (m, 5H), 6.75 (1H, bd), 5.12 (2H, AB), 5.0 (1H, bs),4.15-3.72 (m, 2H), 3.06 (1H, d), 1.60-1.30 (m, 2H), 1.60-1.30 (m, 5H),1.12 (3H, d), 0.97-0.87(6H, dd); Electrospray mass spec: M+H⁺=492.0

i.[(S)-1-((3S,4S,7R)-3-Hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamicacid tert-butyl ester and[(S)-1-((3R,4R,7S)-3-Hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamicacid tert-butyl ester

(2R,5S,6S)-5-((S)-2-tert-Butoxycarbonylamino-4-methyl-pentanoylamino)-6-hydroxy-2-methyl-azepane-1-carboxylicacid benzyl ester and(2S,5R,6R)-5-((S)-2-tert-butoxycarbonylamino-4-methyl-pentanoylamino)-6-hydroxy-2-methyl-azepane-1-carboxylicacid benzyl ester (0.77 g, 1.57 mmol) was dissolved in EtOAc (27.5 ml),MeOH (5.5 ml). Then 10% Pd/C (0.39 g) was added and the reaction wasstirred overnight under a balloon filled with hydrogen gas. The reactionmixture was filtered through Celite, concentrated in vacuo by rotaryevaporation and was used in the next reaction without furtherpurification (0.56 g): Electrospray mass spec: M+H⁺=358.11.

j.[(S)-1-((3S,4S,7R)-1-Benzenesulfonyl-3-hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamicacid tert-butyl ester and[(S)-1-((3R,4R,7S)-1-Benzenesulfonyl-3-hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamicacid tert-butyl ester

2-Pyridine sulfonyl chloride (0.6 g, 3.4 mmol) was added to a solutionof[(S)-1-((3S,4S,7R)-3-Hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamicacid tert-butyl ester and[(S)-1-((3R,4R,7S)-3-hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamicacid tert-butyl ester (1.0 g, 2.8 mmol), N-methyl morpholine (0.45 ml,4.1 mmol) in CH₂Cl₂ (35 ml) and was stirred at RT overnight. Thereaction mixture was diluted with EtOAc (100 ml), washed with H₂O,brine, dried with magnesium sulfate, filtered, concentrated in vacuo byrotary evaporation, and chromatographed (silica gel, 2.5% MeOH/CH₂Cl₂)to yield the title compound (0.9 g, 64%): 1H NMR: 8.68 (m, 1H), 8.05(1H, d), 7.92 (1H, dd), 7.50 (1H, dd), 6.66 (1H, bd), 4.95-4.88 (dd),4.20-3.87 (m, 3H), 3.65 (1H, bs), 3.40 (1H, d), 1.94-1.57 (m, 4H),1.45-1.38 (m, 6H), 1.14 (3H, dd), 0.94 (6H, dd); Electrospray mass spec:M+H⁺=499.0

k. (S)-2-Amino-4-methyl-pentanoic acid((3S,4S,7R)-1-(2-pyridine)-sulfonyl-3-hydroxy-7-methyl-azepan-4-yl)-amideand (S)-2-Amino-4-methyl-pentanoic acid((3R,4R,7S)-1-(2-pyridine)-sulfonyl-3-hydroxy-7-methyl-azepan-4-yl)-amide

HCl in dioxane (4.0 M, 15 ml) was added to a stirred solution of[(S)-1-((3S,4S,7R)-1-benzenesulfonyl-3-hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamicacid tert-butyl ester and[(S)-1-((3R,4R,7S)-1-benzenesulfonyl-3-hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamicacid tert-butyl ester (0.9 g, 1.8 mmol) in MeOH (15 ml). The reactionmixture was stirred for 2 h at RT, then was concentrated in vacuo byrotary evaporation and was used in the next reaction without furtherpurification (0.85 g).

l. Benzofuran-2-carboxylic acid{(S)-1-[(3S,4S,7R)-3-hydroxy-7-methyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amideand benzofuran-2-carboxylic acid{(S)-1-[(3R,4R,7S)-3-hydroxy-7-methyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (0.35 g, 1.85 mmol) wasadded to a solution of 2-benzofuran-carboxylic acid (0.3 g, 1.85 mmol),(S)-2-amino-4-methyl-pentanoic acid((3S,4S,7R)-1-(2-pyridine)-sulfonyl-3-hydroxy-7-methyl-azepan-4-yl)-amideand (S)-2-amino-4methyl-pentanoic acid((3R,4R,7S)-1-(2-pyridine)-sulfonyl-3-hydroxy-7-methyl-azepan-4-yl)-amide(0.85 g, 1.8 mmol), diisopropylethylamine (0.48 g, 0.65 ml, 3.7 mmol),hydroxybenztriazole (0.25 g, 1.85 mmol) in DMF (10 ml) and was stirredat RT overnight. The reaction mixture was then warmed to RT and wasstirred overnight. The reaction mixture was diluted with EtOAc (100 ml),washed with H₂O, brine, dried with magnesium sulfate, filtered,concentrated in vacuo by rotary evaporation, and chromatographed (silicagel, 2.5% MeOH/CH₂Cl₂) to yield the title compound (0.8 g, 82%): 1H NMR:8.65 (m, 1H), 8.05 (m, 1H), 7.87 (dd, 1H), 7.62 (dd, 1H), 7.50-7.35 (m,3H), 7.28-7.20 (m, 1H), 7.07 (m, 1H), 6.92 (1H, bd), 6.80 (bd, 1H),4.65-4.48 (m, 1H), 4.20-3.87 (m, 3H), 3.65 (1H, bd), 3.40 (1H, dd),1.94-1.57 (m, 4H), 1.45-1.38 (m, 6H), 1.14 (3H, dd), 0.94 (6H, m);Electrospray mass spec: M+H⁺=542.98

m. Benzofuran-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amideand Benzofuran-2-carboxylic acid{(S)-3-methyl-1-[(4R,7S)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

Dess-Martin periodinane (1.0 g, 2.36 mmol) was added to a solution ofbenzofuran-2-carboxylic acid{(S)-1-[(3S,4S,7R)-3-hydroxy-7-methyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amideand benzofuran-2-carboxylic acid{(S)-1-[(3R,4R,7S)-3-hydroxy-7-methyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide(0.8 g, 1.48 mmol) in CH₂Cl₂ (20 ml) and was stirred at RT for 45minutes. The solution was washed with 10% NaHCO₃ and brine. Purificationby column chromatography (60% ethyl acetate/hexanes) gave the titlecompound as a mixture of diasteromers (0.75 g, 94%); The diastereomerswere separated by HPLC. Diastereomer 1:1H NMR: 8.72 (m, 1H), 8.0 (d,1H), 8.92 (dd, 1H), 7.65 (d, 1H), 7.56 (d, 1H), 7.45 (s, 1H), 7.42 (dd,2H), 7.28 (d, 1H), 7.10 (d, 1H), 5.15 (m, 1H), 4.77 (d, 1H), 4.68 (m,1H), 4.40 (m, 1H), 3.86 (d, 1H), 2.20-2.08 (m, 2H), 1.78-1.50 (m, 5H),1.22 (dd, 3H), 0.98 (m, 6H); Electrospray mass spec: M+H⁺=541.2;Diastereomer 2:1H NMR: 8.68 (m, 1H), 8.04 (d, 1H), 8.92 (dd, 1H), 7.68(d, 1H), 7.58 (d, 2H), 7.52 (s, 1H), 7.42 (dd, 1H), 7.29 (d, 1H), 7.05(m, 2H), 5.12 (m, 1H), 4.75-4.68 (m, 1H), 4.43 (m, 1H), 3.83 (d, 1H),2.25-2.12 (m, 2H), 1.88-1.50 (m, 5H), 0.98 (m, 9H); Electrospray massspec: M+H⁺=541.2

Example 6 Preparation of Single Diasteromer

Benzofuran-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

a. ((R)-2-Iodo-1-methyl-ethyl)-carbamic acid benzyl ester

Triphenylphospine (24 g, 91.8 mmol) was added to a solution of imidazole(12.5 g, 184 mmol) in CH₂Cl₂ (231 ml), then was cooled to 0 degrees C.Iodine (23.3 g, 91.8 mmol) was added to the suspension. The reactionmixture turned yellow, then faintly brown. After 5 minutes((R)-2-hydroxy-1-methyl-ethyl)-carbamic acid benzyl ester (9.59 g, 45.9mmol) was added and the reaction mixture was warmed to RT then stirredfor 3 h. Then, H₂O (7 ml) was added and the reaction mixture waspartitioned between CH₂Cl₂ (300 ml) and H₂O (600 ml). The aqueous layerwas extracted again with CH₂Cl₂ (200 ml). The combined organic layer wasthen washed with a solution of 1:9 aq. saturated Na₂S₂O₃: H₂O (140 ml),then brine (400 ml). The combined organics were dried with MgSO₄,filtered, concentrated in vacuo, then filtered through a plug of silicagel washing with 15% EtOAc/hexanes (1.5 liter). The solution wasconcentrated in vacuo, then the solid was washed with hexane and theresultant white solid was used in the next reaction without furtherpurification (11 g, 75%).

b. ((R)-1-Methyl-pent-4-enyl)-carbamic acid benzyl ester

Copper (I) bromide-dimethyl sulfide (1.93 g, 9.4 mmol) was dissolved indistilled THF (24 ml), then was cooled to −78 degrees C. A solution ofallyl magnesium chloride (9.4 ml, 2M in THF, Aldrich) was addeddropwise, then the solution was stirred for 30 minutes.((R)-2-Iodo-1-methyl-ethyl)-carbamic acid benzyl ester (1.5 g, 4.7 mmol)in distilled THF (3 ml) was added dropwise, then the reaction was warmedto −40 degrees C. and was stirred for 2.5 h. The reaction mixture wasquenched with aq. sat. NH₄Cl (4 ml) at −40 degrees C., warmed to RT andthe gray reaction mixture turned sky blue. THF was removed in vacuo.Then, Et₂O was added and the reaction mixture was filtered to removeprecipitated solids. The solids were washed with additional Et₂O. Thecombined organics were extracted with 10% NH₄OH (3×), then brine. Thecombined organics were dried with MgSO₄, filtered, concentrated invacuo, then filtered through a plug of silica gel washing with 20%EtOAc/hexanes (100 ml). The solution was concentrated in vacuo, then theresultant colorless oil was used in the next reaction without furtherpurification (0.8 g, 73%).

c. Allyl-((R)-1-methyl-pent-4-enyl)-carbamic acid benzyl ester

((R)-1-Methyl-pent-4-enyl)-carbamic acid benzyl ester (790 mg, 3.39mmol) was dissolved in DMF (8 ml) and was cooled to 0 degrees C. Sodiumhydride (60% dispersion, 271 mg, 6.78 mmol) was added and the reactionwas stirred for 15 minutes. Allyl bromide (1.23 g, 0.88 ml, 10.17 mmol)was added and the reaction mixture was stirred for 3 h at 0 degrees C.H₂O (10 ml) was added, then 2N HCl was added dropwise adjusting the pHto 1. The reaction mixture was extracted with Et₂O (2×50 ml). Thecombined organics were washed with aq. 2N HCl, then aq. NaHCO₃, thenbrine. The combined organics were dried with MgSO₄, filtered,concentrated in vacuo, then chromatographed on silica gel (5%EtOAc/hexanes) to yield the title compound as a colorless oil (883 mg,95%).

d. 2-Methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester

Allyl-(1-methyl-pent-4-enyl)-carbamic acid benzyl ester (0.872 g, 3.19mmol) was dissolved in CH₂Cl₂ (10 ml) and a stream of argon gas wasbubbled into the reaction mixture for 10 minutes. Thenbis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride (StremChemicals, Grubbs' catalyst, 19 mg, 0.0227 mmol) was added and thereaction mixture was refluxed for 2 h. Additionalbis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride (mg,0.0108 mmol) was added and the reaction mixture was refluxed for anadditional 1.5 hours. The reaction was cooled to RT under argonovernight, then was concentrated in vacuo by rotary evaporation, thenwas chromatographed (silica gel, 5% EtOAc/hexanes) to give the titlecompound (0.72 g, 92%): 1H NMR: 7.35-7.20 (m, 5H), 5.65 (1H, m), 5.13(2H, AB), 4.45-4.05 (m, 2H), 3.56 (1H, d), 2.25-2.10 (m, 2H), 1.90-1.60(m, 2H), 1.12 (3H, d); Liquid Chromatgraphy/Electrospray mass spec:M+H⁺=246.2.

e. (1S,4R,7R)-4-Methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylicacid benzyl ester

m-Chloro-perbenzoic acid (1.10 g, 57-86% pure) was added to a solutionof 2-methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester(0.72 g, 2.94 mmol) in CH₂Cl₂ at 0 degrees C. The reaction mixture wasstirred for half an hour, then was warmed to RT. Additionalm-chloro-perbenzoic acid (0.660 g, 57-86% pure) was added and thereaction was stirred 2 h. The reaction mixture was concentrated in vacuoby rotary evaporation, then 80 ml of 9:1 hexanes/EtOAc was added and thereaction mixture was filtered. The filtrate was concentrated in vacuo byrotary evaporation, then was chromatographed (silica gel, 20%EtOAc:hexanes) to give(1S,4R,7S)₄-methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acidbenzyl ester (0.450 g, 75%) and the title compound (0.15 g, 25% yield):1H NMR: 7.42-7.22 (m, 5H), 5.13 (2H, s), 4.50-4.15 (m, 2H), 3.27 (1H,d), 3.12-2.95 (1H, m), 2.15-1.70 (m, 2H), 1.47 (m, 2H), 1.12 (3H, d);Liquid Chromatgraphy/Electrospray mass spec: M+H⁺=262.0.

f. (2R,5S,6S)-5-Azido-6-hydroxy-2-methyl-azepane-1-carboxylic acidbenzyl ester

Sodium azide (0.139 g, 2.14 mmol) was added to a solution of(1S,4R,7R)-4-methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acidbenzyl ester (0.186 g, 0.71 mmol) and ammonium chloride (0.114 g, 2.14mmol) in MeOH (1.5 ml) and H₂O (0.15 ml), then was refluxed for 6 h. Thereaction mixture was concentrated in vacuo by rotary evaporation, thenwas diluted with water (5 ml) and extracted with EtOAc (10 ml). Theorganic layer was then extracted with water, brine, dried with MgSO₄,filtered, concentrated in vacuo by rotary evaporation, andchromatographed (silica gel, 20% EtOAc/hexanes) to yield the titlecompound (0.192 g, 89%): 7.39-7.30 (m, 5H), 5.15 (2H, s), 4.10-3.67 (m,2H), 3.10 (1H, d), 1.85-1.53 (m, 4H), 1.09 (3H, d); LiquidChromatgraphy/Electrospray mass spec: M+H⁺=305.2.

g. (2R,5S,6S)-5-Amino-6-hydroxy-2-methyl-azepane-1-carboxylic acidbenzyl ester

Triphenylphosphine (0.25 g, 0.952 mmol) was added to a solution of(2R,5S,6S)-5-azido-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzylester (0.193 g, 0.635 mmol) in THF (10 ml) and H₂O (0.04 ml), then washeated to 45 degrees C. overnight. The reaction mixture was then dilutedwith toluene (100 ml×2) and was azeotroped in vacuo by rotaryevaporation twice. The resulting oil was dissolved in MeOH and HCl inEt₂O and the resulting salt was collected following filtration and wasused in the next reaction without further purification (0.27 g, 90%).

h.(2R,5S,6S)-5-((S)-2-tert-Butoxycarbonylamino-4-methyl-pentanoylamino)-6-hydroxy-2-methyl-azepane-1-carboxylicacid benzyl ester

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (0.164 g, 0.22 mmol) wasadded to a solution of Boc-Leucine-hydrate (0.190 g, 0.76 mmol),diisopropylethylamine (0.164 g, 0.22 ml, 1.27 mmol), hydroxybenztriazole(0.114 g, 0.83 mmol), and racemic(2R,5S,6S)-5-Amino-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzylester (0.27 g, 0.57 mmol) in DMF (3.2 ml). The reaction was stirredovernight at RT, then was diluted with EtOAc (100 ml), washed with H₂O(3×50 ml), brine (50 ml), dried with magnesium sulfate, filtered,concentrated in vacuo by rotary evaporation, and chromatographed (silicagel, 50% EtOAc/hexanes) to yield the title compound (0.218 g, 72%): 1HNMR: 7.40-7.29 (m, 5H), 6.75 (1H, bd), 5.12 (2H, AB), 5.0 (1H, bs),4.15-3.72 (m, 2H), 3.06 (1H, d), 1.60-1.30 (m, 2H), 1.60-1.30 (m, 5H),1.12 (3H, d), 0.97-0.87(6H, dd); Electrospray mass spec: M+H⁺=492.0

i.[(S)-1-((3S,4S,7R)-3-Hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamicacid tert-butyl ester

(2R,5S,6S)-5-((S)-2-tert-Butoxycarbonylamino-4-methyl-pentanoylamino)-6-hydroxy-2-methyl-azepane-1-carboxylicacid benzyl ester (0.169 g, 0.344 mmol) was dissolved in EtOAc (3 ml),MeOH (1 ml). Then 10% Pd/C (0.183 g, 0.172 mmol) was added and thereaction was stirred overnight under a balloon filled with hydrogen gas.The reaction mixture was filtered through Celite, concentrated in vacuoby rotary evaporation and was used in the next reaction without furtherpurification (0.126 g): Electrospray mass spec: M+H⁺=358.11.

j.[(S)-1-((3S,4S,7R)-2-Pyridinesulfonyl-3-hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamicacid tert-butyl ester

2-Pyridine sulfonyl chloride (0.71 g, 0.4 mmol) was added to a solutionof[(S)-1-((3S,4S,7R)-3-hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamicacid tert-butyl ester (0.126 g, 0.344 mmol), sodium bicarbonate (0.87 g,1.03 mmol) in CH₂Cl₂ (3 ml) and H₂O (2 ml) and was stirred at RT for 30minutes. The reaction mixture was diluted with EtOAc (100 ml), washedwith H₂O, brine, dried with magnesium sulfate, filtered, concentrated invacuo by rotary evaporation, and chromatographed (silica gel, 3%MeOH/CH₂Cl₂) to yield the title compound (0.180 g, 70%): 1H NMR: 8.68(m, 1H), 8.05 (1H, d), 7.92 (1H, dd), 7.50 (1H, dd), 6.66 (1H, bd),4.95-4.88 (dd), 4.20-3.87 (m, 3H), 3.65 (1H, bs), 3.40 (1H, d),1.94-1.57 (m, 4H), 1.45-1.38 (m, 6H), 1.14 (3H, dd), 0.94 (6H, dd);Electrospray mass spec: M+H⁺=499.0

k. (S)-2-Amino-4-methyl-pentanoic acid((3S,4S,7R)-1-(2-pyridine)-sulfonyl-3-hydroxy-7-methyl-azepan-4-yl)-amide

HCl in dioxane (4.0 M, 1.5 ml) was added to a stirred solution of[(S)-1-((3S,4S,7R)-2-pyridinesulfonyl-3-hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamicacid tert-butyl ester (0.090 g, 0.18 mmol) in MeOH (1.5 ml). Thereaction mixture was stirred for 2 h at RT, then was concentrated invacuo by rotary evaporation and was used in the next reaction withoutfurther purification (0.072 g).

l. Benzofuran-2-carboxylic acid{(S)-1-[(3S,4S,7R)-3-hydroxy-7-methyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (0.046 g, 0.36 mmol) wasadded to a solution of 2-benzofuran-carboxylic acid (0.032 g, 0.198mmol), (S)-2-Amino-4-methyl-pentanoic acid((3S,4S,7R)-1-(2-pyridine)-sulfonyl-3-hydroxy-7-methyl-azepan-4-yl)-amide(0.072 g, 0.18 mmol), diisopropylethylamine (0.046 g, 0.06 ml, 0.36mmol), hydroxybenztriazole (0.029 g, 0.36 mmol) in DMF (2 ml) and wasstirred at RT overnight. The reaction mixture was then warmed to RT andwas stirred overnight. The reaction mixture was diluted with EtOAc (10ml), washed with H₂O, brine, dried with magnesium sulfate, filtered,concentrated in vacuo by rotary evaporation, and chromatographed (silicagel, 2.5% MeOH/CH₂Cl₂) to yield the title compound (0.092 g, 94%): 1HNMR: 8.65 (m, 1H), 8.05 (m, 1H), 7.87 (dd, 1H), 7.62 (dd, 1H), 7.50-7.35(m, 3H), 7.28-7.20 (m, 1H), 7.07 (m, 1H), 6.92 (1H, bd), 6.80 (bd, 1H),4.65-4.48 (m, 1H), 4.20-3.87 (m, 3H), 3.65 (1H, bd), 3.40 (1H, dd),1.94-1.57 (m, 4H), 1.45-1.38 (m, 6H), 1.14 (3H, dd), 0.94 (6H, m);Electrospray mass spec: M+H⁺=542.98

m. Benzofuran-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

Dess-Martin periodinane (0.077 g, 0.182 mmol) was added to a solution ofBenzofuran-2-carboxylic acid{(S)-1-[(3S,4S,7R)-3-hydroxy-7-methyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide(0.058 g, 0.107 mmol) in CH₂Cl₂ (10 ml) and was stirred at RT for 1 h.The solution was washed with 10% aq. Na₂S₂O₃, then aq. sat. NaHCO₃, thenbrine. Purification by column chromatography (50% to 80% ethylacetate/hexanes) gave the title compound (0.056 g, 97%): 1H NMR: 8.72(m, 1H), 8.0 (d, 1H), 8.92 (dd, 1H), 7.65 (d, 1H), 7.56 (d, 1H), 7.45(s, 1H), 7.42 (dd, 2H), 7.28 (d, 1H), 7.10 (d, 1H), 5.15 (m, 1H), 4.77(d, 1H), 4.68 (m, 1H), 4.40 (m, 1H), 3.86 (d, 1H), 2.20-2.08 (m, 2H),1.78-1.50 (m, 5H), 1.22 (dd, 3H), 0.98 (m, 6H); Electrospray mass spec:M+H⁺=541.2.

Example 7 2,2,4-Trideutero-benzofuran-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

Benzofuran-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amideis dissolved in d4-methanol (CD₃OD) and D₂O (10:1), then triethyl amineis added and the reaction mixture is stirred for 3 days. Azeotropingwith toluene by concentrating in vacuo provides the title compound.

Example 8 Furo[3,2-b]pyridine-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

a. ((R)-2-Iodo-1-methyl-ethyl)-carbamic acid benzyl ester

Triphenylphospine (24 g, 91.8 mmol) was added to a solution of imidazole(12.5 g, 184 mmol) in CH₂Cl₂ (231 ml), then was cooled to 0 degrees C.Iodine (23.3 g, 91.8 mmol) was added to the suspension. The reactionmixture turned yellow, then faintly brown. After 5 minutes((R)-2-hydroxy-1-methyl-ethyl)-carbamic acid benzyl ester (9.59 g, 45.9mmol) was added and the reaction mixture was warmed to RT then stirredfor 3 h. Then, H₂O (7 ml) was added and the reaction mixture waspartitioned between CH₂Cl₂ (300 ml) and H₂O (600 ml). The aqueous layerwas extracted again with CH₂Cl₂ (200 ml). The combined organic layer wasthen washed with a solution of 1:9 aq. saturated Na₂S₂O₃: H₂O (140 ml),then brine (400 ml). The combined organics were dried with MgSO₄,filtered, concentrated in vacuo, then filtered through a plug of silicagel washing with 15% EtOAc/hexanes (1.5 liter). The solution wasconcentrated in vacuo, then the solid was washed with hexane and theresultant white solid was used in the next reaction without furtherpurification (11 g, 75%).

b. ((R)-1-Methyl-pent-4-enyl)-carbamic acid benzyl ester

Copper (I) bromide-dimethyl sulfide (1.93 g, 9.4 mmol) was dissolved indistilled THF (24 ml), then was cooled to −78 degrees C. A solution ofallyl magnesium chloride (9.4 ml, 2M in THF, Aldrich) was addeddropwise, then the solution was stirred for 30 minutes.((R)-2-Iodo-1-methyl-ethyl)-carbamic acid benzyl ester (1.5 g, 4.7 mmol)in distilled THF (3 ml) was added dropwise, then the reaction was warmedto −40 degrees C. and was stirred for 2.5 h. The reaction mixture wasquenched with aq. sat. NH₄Cl (4 ml) at −40 degrees C., warmed to RT andthe gray reaction mixture turned sky blue. THF was removed in vacuo.Then, Et₂O was added and the reaction mixture was filtered to removeprecipitated solids. The solids were washed with additional Et₂O. Thecombined organics were extracted with 10% NH₄OH (3×), then brine. Thecombined organics were dried with MgSO₄, filtered, concentrated invacuo, then filtered through a plug of silica gel washing with 20%EtOAc/hexanes (100 ml). The solution was concentrated in vacuo, then theresultant colorless oil was used in the next reaction without furtherpurification (0.8 g, 73%).

c. Allyl-((R)-1-methyl-pent-4-enyl)-carbamic acid benzyl ester

((R)-1-Methyl-pent-4-enyl)-carbamic acid benzyl ester (790 mg, 3.39mmol) was dissolved in DMF (8 ml) and was cooled to 0 degrees C. Sodiumhydride (60% dispersion, 271 mg, 6.78 mmol) was added and the reactionwas stirred for 15 minutes. Allyl bromide (1.23 g, 0.88 ml, 10.17 mmol)was added and the reaction mixture was stirred for 3 h at 0 degrees C.H₂O (10 ml) was added, then 2N HCl was added dropwise adjusting the pHto 1. The reaction mixture was extracted with Et₂O (2×50 ml). Thecombined organics were washed with aq. 2N HCl, then aq. NaHCO₃, thenbrine. The combined organics were dried with MgSO₄, filtered,concentrated in vacuo, then chromatographed on silica gel (5%EtOAc/hexanes) to yield the title compound as a colorless oil (883 mg,95%).

d. 2-Methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester

Allyl-(1-methyl-pent-4-enyl)-carbamic acid benzyl ester (0.872 g, 3.19mmol) was dissolved in CH₂Cl₂ (10 ml) and a stream of argon gas wasbubbled into the reaction mixture for 10 minutes. Thenbis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride (StremChemicals, Grubbs' catalyst, 19 mg, 0.0227 mmol) was added and thereaction mixture was refluxed for 2 h. Additionalbis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride (mg,0.0108 mmol) was added and the reaction mixture was refluxed for anadditional 1.5 hours. The reaction was cooled to RT under argonovernight, then was concentrated in vacuo by rotary evaporation, thenwas chromatographed (silica gel, 5% EtOAc/hexanes) to give the titlecompound (0.72 g, 92%): 1H NMR: 7.35-7.20 (m, 5H), 5.65 (1H, m), 5.13(2H, AB), 4.45-4.05 (m, 2H), 3.56 (1H, d), 2.25-2.10 (m, 2H), 1.90-1.60(m, 2H), 1.12 (3H, d); Liquid Chromatgraphy/Electrospray mass spec:M+H⁺=246.2.

e. (1S,4R,7R)-4-Methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylicacid benzyl ester

m-Chloro-perbenzoic acid (1.10 g, 57-86% pure) was added to a solutionof 2-methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester(0.72 g, 2.94 mmol) in CH₂Cl₂ at 0 degrees C. The reaction mixture wasstirred for half an hour, then was warmed to RT. Additionalm-chloro-perbenzoic acid (0.660 g, 57-86% pure) was added and thereaction was stirred 2 h. The reaction mixture was concentrated in vacuoby rotary evaporation, then 80 ml of 9:1 hexanes/EtOAc was added and thereaction mixture was filtered. The filtrate was concentrated in vacuo byrotary evaporation, then was chromatographed (silica gel, 20%EtOAc:hexanes) to give(1S,4R,7S)₄-methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acidbenzyl ester (0.450 g, 75%) and the title compound (0.15 g, 25% yield):1H NMR: 7.42-7.22 (m, 5H), 5.13 (2H, s), 4.50-4.15 (m, 2H), 3.27 (1H,d), 3.12-2.95 (1H, m), 2.15-1.70 (m, 2H), 1.47 (m, 2H), 1.12 (3H, d);Liquid Chromatgraphy/Electrospray mass spec: M+H⁺=262.0.

f. (2R,5S,6S)-5-Azido-6-hydroxy-2-methyl-azepane-1-carboxylic acidbenzyl ester

Sodium azide (0.139 g, 2.14 mmol) was added to a solution of(1S,4R,7R)-4-methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acidbenzyl ester (0.186 g, 0.71 mmol) and ammonium chloride (0.114 g, 2.14mmol) in MeOH (1.5 ml) and H₂O (0.15 ml), then was refluxed for 6 h. Thereaction mixture was concentrated in vacuo by rotary evaporation, thenwas diluted with water (5 ml) and extracted with EtOAc (10 ml). Theorganic layer was then extracted with water, brine, dried with MgSO₄,filtered, concentrated in vacuo by rotary evaporation, andchromatographed (silica gel, 20% EtOAc/hexanes) to yield the titlecompound (0.192 g, 89%): 7.39-7.30 (m, 5H), 5.15 (2H, s), 4.10-3.67 (m,2H), 3.10 (1H, d), 1.85-1.53 (m, 4H), 1.09 (3H, d); LiquidChromatgraphy/Electrospray mass spec: M+H⁺=305.2.

g. (2R,5S,6S)-5-Amino-6-hydroxy-2-methyl-azepane-1-carboxylic acidbenzyl ester

Triphenylphosphine (0.25 g, 0.952 mmol) was added to a solution of(2R,5S,6S)-5-azido-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzylester (0.193 g, 0.635 mmol) in THF (10 ml) and H₂O (0.04 ml), then washeated to 45 degrees C. overnight. The reaction mixture was then dilutedwith toluene (100 ml×2) and was azeotroped in vacuo by rotaryevaporation twice. The resulting oil was dissolved in MeOH and HCl inEt₂O and the resulting salt was collected following filtration and wasused in the next reaction without further purification (0.27 g, 90%).

h.(2R,5S,6S)-5-((S)-2-tert-Butoxycarbonylamino-4-methyl-pentanoylamino)-6-hydroxy-2-methyl-azepane-1-carboxylicacid benzyl ester

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (0.164 g, 0.22 mmol) wasadded to a solution of Boc-Leucine-hydrate (0.190 g, 0.76 mmol),diisopropylethylamine (0.164 g, 0.22 ml, 1.27 mmol), hydroxybenztriazole(0.114 g, 0.83 mmol), and racemic(2R,5S,6S)-5-Amino-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzylester (0.27 g, 0.57 mmol) in DMF (3.2 ml). The reaction was stirredovernight at RT, then was diluted with EtOAc (100 ml), washed with H₂O(3×50 ml), brine (50 ml), dried with magnesium sulfate, filtered,concentrated in vacuo by rotary evaporation, and chromatographed (silicagel, 50% EtOAc/hexanes) to yield the title compound (0.218 g, 72%): 1HNMR: 7.40-7.29 (m, 5H), 6.75 (1H, bd), 5.12 (2H, AB), 5.0 (1H, bs),4.15-3.72 (m, 2H), 3.06 (1H, d), 1.60-1.30 (m, 2H), 1.60-1.30 (m, 5H),1.12 (3H, d), 0.97-0.87(6H, dd); Electrospray mass spec: M+H⁺=492.0

i.[(S)-1-((3S,4S,7R)-3-Hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamicacid tert-butyl ester

(2R,5S,6S)-5-((S)-2-tert-Butoxycarbonylamino-4-methyl-pentanoylamino)-6-hydroxy-2-methyl-azepane-1-carboxylicacid benzyl ester (0.169 g, 0.344 mmol) was dissovled in EtOAc (3 ml),MeOH (1 ml). Then 10% Pd/C (0.183 g, 0.172 mmol) was added and thereaction was stirred overnight under a balloon filled with hydrogen gas.The reaction mixture was filtered through Celite, concentrated in vacuoby rotary evaporation and was used in the next reaction without furtherpurification (0.126 g): Electrospray mass spec: M+H⁺=358.11.

j.[(S)-1-((3S,4S,7R)-2-Pyridinesulfonyl-3-hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamicacid tert-butyl ester

2-Pyridine sulfonyl chloride (0.71 g, 0.4 mmol) was added to a solutionof.[(S)-1-((3S,4S,7R)-3-Hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamicacid tert-butyl ester (0.126 g, 0.344 mmol), sodium bicarbonate (0.87 g,1.03 mmol) in CH₂Cl₂ (3 ml) and H₂O (2 ml) and was stirred at RT for 30minutes. The reaction mixture was diluted with EtOAc (100 ml), washedwith H₂O, brine, dried with magnesium sulfate, filtered, concentrated invacuo by rotary evaporation, and chromatographed (silica gel, 3%MeOH/CH₂Cl₂) to yield the title compound (0.180 g, 70%): 1H NMR: 8.68(m, 1H), 8.05 (1H, d), 7.92 (1H, dd), 7.50 (1H, dd), 6.66 (1H, bd),4.95-4.88 (dd), 4.20-3.87 (m, 3H), 3.65 (1H, bs), 3.40 (1H, d),1.94-1.57 (m, 4H), 1.45-1.38 (m, 6H), 1.14 (3H, dd), 0.94 (6H, dd);Electrospray mass spec: M+H⁺=499.0

k. (S)-2-Amino-4-methyl-pentanoic acid((3S,4S,7R)-1-(2-pyridine)-sulfonyl-3-hydroxy-7-methyl-azepan-4-yl)-amide

HCl in dioxane (4.0 M, 1.5 ml) was added to a stirred solution of[(S)-1-((3S,4S,7R)-2-pyridinesulfonyl-3-hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamicacid tert-butyl ester (0.090 g, 0.18 mmol) in MeOH (1.5 ml). Thereaction mixture was stirred for 2 h at RT, then was concentrated invacuo by rotary evaporation and was used in the next reaction withoutfurther purification (0.072 g).

l. Furo[3,2-b]pyridine-2-carboxylic acid{(S)-1-[(3S,4S,7R)-3-hydroxy-7-methyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (0.035 g, 0.185 mmol) wasadded to a solution of Furo[3,2-b]pyridine-2-carboxylic acid (0.034 g,0.2 mmol, as described in Shiotani, Shunsaku; Morita, Hiroyuki J.Heterocycl. Chem. 1991, 28 (6), 1469-1480),(S)-2-Amino-4-methyl-pentanoic acid((3S,4S,7R)-1-(2-pyridine)-sulfonyl-3-hydroxy-7-methyl-azepan-4-yl)-amide(0.077 g, 0.16 mmol), diisopropylethylamine (0.05 g, 0.07 ml, 0.4 mmol),hydroxybenztriazole (0.025 g, 0.185 mmol) in DMF (1.5 ml) and wasstirred at RT overnight. The reaction mixture was then warmed to RT andwas stirred overnight. The reaction mixture was diluted with EtOAc (20ml), washed with H₂O, brine, dried with magnesium sulfate, filtered,concentrated in vacuo by rotary evaporation, and chromatographed (silicagel, 2.5% MeOH/CH₂Cl₂) to yield the title compound (0.056 g, 64%): 1HNMR: 8.68 (1H, d), 7.96 (1H, d), 7.87 (1H, d), 7.82 (1H, dd), 7.65 (1H,d), 7.61 (1H, s), 7.45 (1H, dd), 7.33 (1H, dd), 7.08 (d, 1H), 4.69 (q,1H), 3.90-3.45 (m, 3H), 3.71 (q, 1H), 3.12-3.04 (m, 1H), 2.04-1.95 (m,1H), 1.88-1.65 (m, 3H), 1.55-1.45 (m, 2H), 0.95 (m, 9H); Electrospraymass spec: M+H⁺=543.86

m. Furo[3,2-b]pyridine-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

Sulfur trioxide-pyridine complex (0.050 g, 0.31 mmol) was added to asolution of Furo[3,2-b]pyridine-2-carboxylic acid{(S)-1-[(3S,4S,7R)-3-hydroxy-7-methyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide(0.056 g, 0.103 mmol) in DMSO (1.0 ml) and triethylamine (0.085 ml, 0.6mmol) was stirred at RT for 1 h. The reaction was incomplete; therefore,additional triethyl amine (0.04 ml, 0.3 mmol) and sulfurtrioxide-pyridine complex (0.0.025 g, 0.15 mmol) was added ant thereaction was stirred an additional hour. The reaction mixture wasdiluted with water, then was extracted with EtOAc. Then, the organiclayer was was extracted with brine. The combined organics were driedwith magnesium sulfate, filtered, concentrated in vacuo, and purified bycolumn chromatography (50% to 80% ethyl acetate/hexanes) gave the titlecompound (12.5 mg, 22%): 1H NMR: 1H NMR: 8.72 (1H, d), 8.66 (1H, d),8.02 (1H, d), 7.93 (1H, dd), 7.85 (1H, d), 7.53 (1H, dd), 7.40 (1H, dd),7.25 (d, 1H), 6.95 (1H, d), 5.15 (m, 1H), 4.77 (m, 2H), 3.72 (q, 1H),2.20-2.08 (m, 2H), 1.78-1.50 (m, 5H), 1.22 (dd, 3H), 0.98 (m, 6H);Electrospray mass spec: M+H⁺=542.2

Example 9 Preparation of2,2,4-Trideutero-furo[3,2-b]pyridine-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

Furo[3,2-b]pyridine-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amideis dissolved in d4-methanol (CD₃OD) and D₂O (10:1), then triethyl amineis added and the reaction mixture is stirred for 3 days. Azeotropingwith toluene by concentrating in vacuo provides the title compound.

Example 10 Preparation of 3-methyl-furo[3,2-b]pyridine-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

Following the procedure of Example 8 (a-m), except substituting“3-methyl-furo[3,2-b]pyridine-2-carboxylic acid (as described inShiotani, Shunsaku; Morita, Hiroyuki J. Heterocycl. Chem. 1991, 28 (6),1469-1480)” for “furo[3,2-b]pyridine-2-carboxylic acid” gave the titlecompound: MS (M+H+); 1H NMR: 8.72 (d, 1H), 8.66 (d, 1H), 8.02 (d, 1H),7.93 (dd, 1H), 7.80 (d, 1H), 7.53 (dd, 1H), 7.39 (dd, 1H), 7.66 (d, 1H),6.90 (d, 1H), 5.56-5.12 (m, 1H), 4.72 (q, 1H), 4.42 (q, 1H), 3.87 (d,1H), 2.70 (s, 3H), 2.24-2.14 (m, 2H), 1.75 (m, 2H), 1.65-1.42 (m, 4H),1.2-0.95 (m, 9H); Electrospray mass spec: M+H⁺=556.2.

Example 11 Preparation of2,2,4-Trideutero-3-methyl-furo[3,2-b]pyridine-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

Following the procedure of Example 9, except substituting3-methyl-furo[3,2-b]pyridine-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide”for “furo[3,2-b]pyridine-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide”gives the title compound.

Example 12 Preparation of Quinoline-6-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

a. ((R)-2-Iodo-1-methyl-ethyl)-carbamic acid benzyl ester

Triphenylphospine (24 g, 91.8 mmol) was added to a solution of imidazole(12.5 g, 184 mmol) in CH₂Cl₂ (231 ml), then was cooled to 0 degrees C.Iodine (23.3 g, 91.8 mmol) was added to the suspension. The reactionmixture turned yellow, then faintly brown. After 5 minutes((R)-2-hydroxy-1-methyl-ethyl)-carbamic acid benzyl ester (9.59 g, 45.9mmol) was added and the reaction mixture was warmed to RT then stirredfor 3 h. Then, H₂O (7 ml) was added and the reaction mixture waspartitioned between CH₂Cl₂ (300 ml) and H₂O (600 ml). The aqueous layerwas extracted again with CH₂Cl₂ (200 ml). The combined organic layer wasthen washed with a solution of 1:9 aq. saturated Na₂S₂O₃: H₂O (140 ml),then brine (400 ml). The combined organics were dried with MgSO₄,filtered, concentrated in vacuo, then filtered through a plug of silicagel washing with 15% EtOAc/hexanes (1.5 liter). The solution wasconcentrated in vacuo, then the solid was washed with hexane and theresultant white solid was used in the next reaction without furtherpurification (11 g, 75%).

b. ((R)-1-Methyl-pent-4-enyl)-carbamic acid benzyl ester

Copper (I) bromide-dimethyl sulfide (1.93 g, 9.4 mmol) was dissolved indistilled THF (24 ml), then was cooled to −78 degrees C. A solution ofallyl magnesium chloride (9.4 ml, 2M in THF, Aldrich) was addeddropwise, then the solution was stirred for 30 minutes.((R)-2-Iodo-1-methyl-ethyl)-carbamic acid benzyl ester (1.5 g, 4.7 mmol)in distilled THF (3 ml) was added dropwise, then the reaction was warmedto −40 degrees C. and was stirred for 2.5 h. The reaction mixture wasquenched with aq. sat. NH₄Cl (4 ml) at −40 degrees C., warmed to RT andthe gray reaction mixture turned sky blue. THF was removed in vacuo.Then, Et₂O was added and the reaction mixture was filtered to removeprecipitated solids. The solids were washed with additional Et₂O. Thecombined organics were extracted with 10% NH₄OH (3×), then brine. Thecombined organics were dried with MgSO₄, filtered, concentrated invacuo, then filtered through a plug of silica gel washing with 20%EtOAc/hexanes (100 ml). The solution was concentrated in vacuo, then theresultant colorless oil was used in the next reaction without furtherpurification (0.8 g, 73%).

c. Allyl-((R)-1-methyl-pent-4-enyl)-carbamic acid benzyl ester

((R)-1-Methyl-pent-4-enyl)-carbamic acid benzyl ester (790 mg, 3.39mmol) was dissolved in DMF (8 ml) and was cooled to 0 degrees C. Sodiumhydride (60% dispersion, 271 mg, 6.78 mmol) was added and the reactionwas stirred for 15 minutes. Allyl bromide (1.23 g, 0.88 ml, 10.17 mmol)was added and the reaction mixture was stirred for 3 h at 0 degrees C.H₂O (10 ml) was added, then 2N HCl was added dropwise adjusting the pHto 1. The reaction mixture was extracted with Et₂O (2×50 ml). Thecombined organics were washed with aq. 2N HCl, then aq. NaHCO₃, thenbrine. The combined organics were dried with MgSO₄, filtered,concentrated in vacuo, then chromatographed on silica gel (5%EtOAc/hexanes) to yield the title compound as a colorless oil (883 mg,95%).

d. 2-Methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester

Allyl-(1-methyl-pent-4-enyl)-carbamic acid benzyl ester (0.872 g, 3.19mmol) was dissolved in CH₂Cl₂ (10 ml) and a stream of argon gas wasbubbled into the reaction mixture for 10 minutes. Thenbis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride (StremChemicals, Grubbs' catalyst, 19 mg, 0.0227 mmol) was added and thereaction mixture was refluxed for 2 h. Additionalbis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride (mg,0.0108 mmol) was added and the reaction mixture was refluxed for anadditional 1.5 hours. The reaction was cooled to RT under argonovernight, then was concentrated in vacuo by rotary evaporation, thenwas chromatographed (silica gel, 5% EtOAc/hexanes) to give the titlecompound (0.72 g, 92%): 1H NMR: 7.35-7.20 (m, 5H), 5.65 (1H, m), 5.13(2H, AB), 4.45-4.05 (m, 2H), 3.56 (1H, d), 2.25-2.10 (m, 2H), 1.90-1.60(m, 2H), 1.12 (3H, d); Liquid Chromatgraphy/Electrospray mass spec:M+H⁺=246.2.

e. (1S,4R,7R)-4-Methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylicacid benzyl ester

m-Chloro-perbenzoic acid (1.10 g, 57-86% pure) was added to a solutionof 2-methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester(0.72 g, 2.94 mmol) in CH₂Cl₂ at 0 degrees C. The reaction mixture wasstirred for half an hour, then was warmed to RT. Additionalm-chloro-perbenzoic acid (0.660 g, 57-86% pure) was added and thereaction was stirred 2 h. The reaction mixture was concentrated in vacuoby rotary evaporation, then 80 ml of 9:1 hexanes/EtOAc was added and thereaction mixture was filtered. The filtrate was concentrated in vacuo byrotary evaporation, then was chromatographed (silica gel, 20%EtOAc:hexanes) to give(1S,4R,7S)₄-methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acidbenzyl ester (0.450 g, 75%) and the title compound (0.15 g, 25% yield):1H NMR: 7.42-7.22 (m, 5H), 5.13 (2H, s), 4.50-4.15 (m, 2H), 3.27 (1H,d), 3.12-2.95 (1H, m), 2.15-1.70 (m, 2H), 1.47 (m, 2H), 1.12 (3H, d);Liquid Chromatgraphy/Electrospray mass spec: M+H⁺=262.0.

f. (2R,5S,6S)-5-Azido-6-hydroxy-2-methyl-azepane-1-carboxylic acidbenzyl ester

Sodium azide (0.139 g, 2.14 mmol) was added to a solution of(1S,4R,7R)-4-methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acidbenzyl ester (0.186 g, 0.71 mmol) and ammonium chloride (0.114 g, 2.14mmol) in MeOH (1.5 ml) and H₂O (0.15 ml), then was refluxed for 6 h. Thereaction mixture was concentrated in vacuo by rotary evaporation, thenwas diluted with water (5 ml) and extracted with EtOAc (10 ml). Theorganic layer was then extracted with water, brine, dried with MgSO₄,filtered, concentrated in vacuo by rotary evaporation, andchromatographed (silica gel, 20% EtOAc/hexanes) to yield the titlecompound (0.192 g, 89%): 7.39-7.30 (m, 5H), 5.15 (2H, s), 4.10-3.67 (m,2H), 3.10 (1H, d), 1.85-1.53 (m, 4H), 1.09 (3H, d); LiquidChromatgraphy/Electrospray mass spec: M+H⁺=305.2.

g. (2R,5S,6S)-5-Amino-6-hydroxy-2-methyl-azepane-1-carboxylic acidbenzyl ester

Triphenylphosphine (0.25 g, 0.952 mmol) was added to a solution of(2R,5S,6S)-5-azido-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzylester (0.193 g, 0.635 mmol) in THF (10 ml) and H₂O (0.04 ml), then washeated to 45 degrees C. overnight. The reaction mixture was then dilutedwith toluene (100 ml×2) and was azeotroped in vacuo by rotaryevaporation twice. The resulting oil was dissolved in MeOH and HCl inEt₂O and the resulting salt was collected following filtration and wasused in the next reaction without further purification (0.27 g, 90%).

h.(2R,5S,6S)-5-((S)-2-tert-Butoxycarbonylamino-4-methyl-pentanoylamino)-6-hydroxy-2-methyl-azepane-1-carboxylicacid benzyl ester

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (0.164 g, 0.22 mmol) wasadded to a solution of Boc-Leucine-hydrate (0.190 g, 0.76 mmol),diisopropylethylamine (0.164 g, 0.22 ml, 1.27 mmol), hydroxybenztriazole(0.114 g, 0.83 mmol), and racemic(2R,5S,6S)-5-Amino-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzylester (0.27 g, 0.57 mmol) in DMF (3.2 ml). The reaction was stirredovernight at RT, then was diluted with EtOAc (100 ml), washed with H₂O(3×50 ml), brine (50 ml), dried with magnesium sulfate, filtered,concentrated in vacuo by rotary evaporation, and chromatographed (silicagel, 50% EtOAc/hexanes) to yield the title compound (0.218 g, 72%): 1HNMR: 7.40-7.29 (m, 5H), 6.75 (1H, bd), 5.12 (2H, AB), 5.0 (1H, bs),4.15-3.72 (m, 2H), 3.06 (1H, d), 1.60-1.30 (m, 2H), 1.60-1.30 (m, 5H),1.12 (3H, d), 0.97-0.87(6H, dd); Electrospray mass spec: M+H⁺=492.0

i.[(S)-1-((3S,4S,7R)-3-Hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamicacid tert-butyl ester

(2R,5S,6S)-5-((S)-2-tert-Butoxycarbonylamino-4-methyl-pentanoylamino)-6-hydroxy-2-methyl-azepane-1-carboxylicacid benzyl ester (0.169 g, 0.344 mmol) was dissovled in EtOAc (3 ml),MeOH (1 ml). Then 10% Pd/C (0.183 g, 0.172 mmol) was added and thereaction was stirred overnight under a balloon filled with hydrogen gas.The reaction mixture was filtered through Celite, concentrated in vacuoby rotary evaporation and was used in the next reaction without furtherpurification (0.126 g): Electrospray mass spec: M+H⁺=358.11.

j.[(S)-1-((3S,4S,7R)-2-Pyridinesulfonyl-3-hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamicacid tert-butyl ester

Pyridine-2-sulfonyl chloride (0.71 g, 0.4 mmol) was added to a solutionof[(S)-1-((3S,4S,7R)-3-Hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamicacid tert-butyl ester (0.126 g, 0.344 mmol), sodium bicarbonate (0.87 g,1.03 mmol) in CH₂Cl₂ (3 ml) and H₂O (2 ml) and was stirred at RT for 30minutes. The reaction mixture was diluted with EtOAc (100 ml), washedwith H₂O, brine, dried with magnesium sulfate, filtered, concentrated invacuo by rotary evaporation, and chromatographed (silica gel, 3%MeOH/CH₂Cl₂) to yield the title compound (0.180 g, 70%): 1H NMR: 8.68(m, 1H), 8.05 (1H, d), 7.92 (1H, dd), 7.50 (1H, dd), 6.66 (1H, bd),4.95-4.88 (dd), 4.20-3.87 (m, 3H), 3.65 (1H, bs), 3.40 (1H, d),1.94-1.57 (m, 4H), 1.45-1.38 (m, 6H), 1.14 (3H, dd), 0.94 (6H, dd);Electrospray mass spec: M+H⁺=499.0

k. (S)-2-Amino-4-methyl-pentanoic acid((3S,4S,7R)-1-(2-pyridine)-sulfonyl-3-hydroxy-7-methyl-azepan-4-yl)-amide

HCl in dioxane (4.0 M, 1.5 ml) was added to a stirred solution of[(S)-1-((3S,4S,7R)-2-pyridinesulfonyl-3-hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamicacid tert-butyl ester (0.090 g, 0.18 mmol) in MeOH (1.5 ml). Thereaction mixture was stirred for 2 h at RT, then was concentrated invacuo by rotary evaporation and was used in the next reaction withoutfurther purification (0.072 g).

l. Quinoline-6-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (76 mg, 0.4 mmol) wasadded to a solution of Quinoline-6-carboxylic acid (64 mg, 0.37 mmol),(S)-2-Amino-4-methyl-pentanoic acid((3S,4S,7R)-1-(2-pyridine)-sulfonyl-3-hydroxy-7-methyl-azepan-4-yl)-amide(160 mg, 0.37 mmol), diisopropylethylamine (56 mg, 0.075 ml, 0.43 mmol),hydroxybenztriazole (50 mg, 0.37 mmol) in DMF (3 ml) and was stirred atRT overnight. The reaction mixture was then warmed to RT and was stirredovernight. The reaction mixture was diluted with EtOAc (20 ml), washedwith H₂O, brine, dried with magnesium sulfate, filtered, concentrated invacuo by rotary evaporation, and chromatographed (silica gel, 4.5%MeOH/CH₂Cl₂) to yield the title compound (138 mg, 69%): 1H NMR: 8.90 (s,1), 8.60 (s, 1H), 8.30 (s, 1H), 7.95-8.10 (m, 4H), 7.85-7.95 (m, 1H),7.70 (d, 1H), 7.35-7.50 (m, 3H), 4.75-4.85 (m, 1H), 4.10 (d, 1H), 4.0(bs, 1H), 3.85 (bs, 1H), 3.80 (s, 1H), 3.45 (d, 1H), 1.60-1.75 (m, 3H),1.40-1.50 (m, 1H), 0.90-1.0 (m, 9H); Electrospray mass spec: M+H⁺=554.28(M+H⁺); 1107.38 (2M+H⁺).

m. Quinoline-6-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

Sulfur trioxide-pyridine complex (11 mg, 0.7 mmol) was added to asolution of quinoline-6-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide(130 mg, 0.235 mmol) in DMSO (2.0 ml) and triethylamine (0.2 ml, 1.4mmol) was stirred at RT for 1 h. The reaction was incomplete; therefore,additional triethyl amine (0.2 ml, 1.4 mmol) and sulfurtrioxide-pyridine complex (11 mg, 0.7 mmol) was added and the reactionwas stirred an additional hour. The reaction mixture was diluted withwater, then was extracted with EtOAc. Then, the organic layer was wasextracted with brine. The combined organics were dried with magnesiumsulfate, filtered, concentrated in vacuo, and purified by columnchromatography (3% MeOH/CH₂Cl₂) gave the title compound (100 mg, 77%):1H NMR:9.0 (sm 1H), 8.70 (s, 1H), 7.90-8.30 (m, 6H), 7.50-7.55 (m, 2H),7.10 (d, 1H), 7.0 (d, 1H), 5.10-5.15 (m, 1H), 4.70-4.80 (m, 2H),4.35-4.40 (m, 1H), 3.85 (d, 1H), 2.0-2.25 (m, 3H), 1.70-1.80 (m, 2H),1.60-1.70 (m, 2H), 0.90-1.10 (m, 9H); Electrospray mass spec: M+H⁺=552.4

Example 13 Preparation of Quinoline-3-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

Following the procedure of Example 12 (a-m), except substituting“quinoline-3-carboxylic acid” for “quinoline-6-carboxylic acid” gave thetitle compound: 1H NMR: 9.30 (s, 1H), 8.70 (s, 1H), 8.60 (s, 1H), 8.20(d, 1H), 7.80-8.0 (m, 4H), 7.65 (t, 1H), 7.50 9d, 1H), 7.20 (d, 1H),7.10 (d, 1H), 5.70-5.85 (m, 2H), 5.10-5.20 (m, 1H), 4.35-4.45 (m, 1H),3.85 (d, 1H), 2.10-2.25 (m, 2H), 1.70-1.80 (m, 3H), 1.45-1.65 (m, 2H),0.90-1.10 (m, 9H); Electrospray mass spec: M+H⁺=552.4.

Example 14 Preparation of 5-Methoxy-benzofuran-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

Following the procedure of Example 12 (a-m), except substituting“5-methoxy-benzofuran-2-carboxylic acid” for “quinoline-6-carboxylicacid” gave the title compound: 1H NMR: 8.73 (d,1H), 7.95(m,2H),7.55(m,1H), 7.43(m,2H), 7.09 (m,3H), 6.93(d,1H), 5.15(m,1H), 4.78(d,1H),4.71(m,1H), 4.43(m,1H), 3.89(d,1H), 3.86(s,3H), 2.18(m,2H),1.56-1.77(m,5H), 0.95(m,9H). Electrospray mass spec: M+H⁺=571.4 (M+H)⁺.

Example 15 Preparation of 3-Methyl-benzofuran-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

Following the procedure of Example 12 (a-m), except substituting“3-methyl-benzofuran-2-carboxylic acid” for “quinoline-6-carboxylicacid” gave the title compound: 1H NMR: 8.74(d,1H), 8.02(d,1H), 7.95(m,1H), 7.62(d,1H), 7.54(m,3H), 7.05(d,1H), 6.93(d,1H), 5.14(m,1H),4.78(d,1H), 4.71(m,1H), 4.43(m,1H), 3.87(d,1H), 2.64(s,3H), 2.19 (m,2H),1.5-1.76(m,5H), 1.0(m, 10H); Electrospray mass spec: M+H⁺=555.2 (M+1)⁺.

Example 16 Preparation of Thieno[3,2-b]thiophene-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

Following the procedure of Example 12 (a-m), except substituting“thieno[3,2-b]thiophene-2-carboxylic acid” for “quinoline-6-carboxylicacid” gave the title compound: 1H NMR: 8.74(d,1H), 8.02(d,1H),7.95(m,1H), 7.78(s,1H), 7.54(m,2H), 6.90(d,1H), 6.59(d,1H), 5.15(m,1H),4.78(d,1H), 4.70(m,1H), 4.43(m,1H), 3.88(d,1H), 2.19(m,2H),1.50-1.72(m.5H), 1.00(m, 10H); Electrospray mass spec: M+H⁺=563.2(M+1)⁺.

Example 17 Preparation of Quinoxaline-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-aide

Following the procedure of Example 12 (a-m), except substituting“quinoxaline-2-carboxylic acid” for “quinoline-6-carboxylic acid” gavethe title compound: 1H NMR: 9.70 (s, 1H), 8.70 (s, 1H), 8.40 (d, 1H),8.20 (d, 2H), 7.85-8.0 (m, 1H), 7.50 (d, 1H), 7.0 (d, 1H), 5.10-5.15 (m,1H), 4.70-4.80 (m, 2H), 4.40-4.50 (m, 1H), 3.90 (d, 1H), 2.10-2.20 (m,2H), 1.70-1.90 (m, 3H), 1.40-1.70 (m, 2H), 0.90-1.05 (m, 9H);Electrospray mass spec: M+H⁺=553.4.

Example 18 Preparation of Thieno[3,2-b]thiophene-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

Following the procedure of Example 12 (a-m), except substituting“1-oxy-pyridine-2-sulfonyl chloride” for “pyridine-2-sulfonyl chloride”and “Thieno[3,2-b]thiophene-2-carboxylic acid” for“quinoline-6-carboxylic acid” gave the title compound: 1H NMR: 8.27 (d,1H), 8.13 (dd, 1H), 7.55-7.41 (m, 3H), 7.28 (m, 2H), 6.95 (m, 1H), 6.65(m, 1H), 5.03 (m, 1H), 4.89 (d, 1H), 4.68 (m, 1H), 4.36 (m, 1H), 3.98(d, 1H), 2.30-2.12 (m, 2H), 1.74 (m, 5H), 1.06 (d, 3H), 1.00 (m, 6H);Electrospray mass spec: M+H⁺=579.2.

Example 19 Preparation of 3-Methyl-benzofuran-2-carboxylicacid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

Following the procedure of Example 12 (a-m), except substituting“1-oxy-pyridine-2-sulfonyl chloride” for “pyridine-2-sulfonyl chloride”and “3-methyl-benzofuran-2-carboxylic acid” for “quinoline-6-carboxylicacid” gave the title compound: 1H NMR: 8.25 (d, 1H), 8.12 (dd, 1H), 7.61(d, 1H), 7.50-7.39 (m, 3H), 7.30 (m, 1H), 7.05 (d, 1H), 6.95 (d, 1H),5.03 (m, 1H), 4.89 (d, 1H), 4.71 (m, 1H), 4.36 (m, 1H), 3.98 (d, 1H),2.62 (s, 3H), 2.25-2.12 (m, 2H), 1.89 (m, 2H), 1.75 (m, 2H), 1.63 (m,1H), 1.53 (m, 1H), 1.05 (d, 3H), 1.00 (m, 6H); Electrospray mass spec:M+H⁺=571.4.

Example 20 Preparation of Benzofuran-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

Following the procedure of Example 12 (a-m), except substituting“1-oxy-pyridine-2-sulfonyl chloride” for “pyridine-2-sulfonyl chloride”and “benzofuran-2-carboxylic acid” for “quinoline-6-carboxylic acid”gave the title compound: 1H NMR: 8.23 (d, 1H), 8.12 (dd, 1H), 7.67 (d,1H), 7.52 (d, 1H), 7.48-7.39 (m, 3H), 7.31 (m, 1H), 7.08 (d, 1H), 6.93(d, 1H), 5.05 (m, 1H), 4.91 (d, 1H), 4.71 (m, 1H), 4.37 (m, 1H), 3.99(d, 1H), 2.30-2.10 (m, 2H), 1.75-1.50 (m, 6H), 1.05 (d, 3H), 1.01 (m,6H); Electrospray mass spec: M+H⁺=557.2.

Example 21 Preparation of Quinoline-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

Following the procedure of Example 12 (a-m), except substituting“1-oxy-pyridine-2-sulfonyl chloride” for “pyridine-2-sulfonyl chloride”and “quinoline-2-carboxylic acid” for “quinoline-6-carboxylic acid” gavethe title compound: 1H NMR: 8.65 (m, 2H), 8.49 (d, 1H), 8.23 (d, 1H),8.11 (d, 1H), 8.05-7.95 (m, 2H), 7.80 (t, 1H), 7.46 (t, 1H), 7.39 (t,1H), 5.02 (m, 1H), 4.85 (d, 1H), 4.75 (m, 1H), 4.39 (m, 1H), 3.93 (d,1H), 2.30-2.08 (m, 3H), 1.97-1.80 (m, 4H), 1.70-1.52 (m, 2H), 1.07-0.99(m, 9H); Electrospray mass spec: M+H⁺=568.2.

Example 22 Preparation of 5,6-Difluoro-benzofuran-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

Following the procedure of Example 12 (a-m), except substituting“1-oxy-pyridine-2-sulfonyl chloride” for “pyridine-2-sulfonyl chloride”and “5,6-Difluoro-benzofuran-2-carboxylic acid” for“quinoline-6-carboxylic acid” gave the title compound: 1H NMR: 8.16 (1H,d), 8.04 (1H,d), 7.26-7.40 (m, 4H), 7.02 (1H, d), 6.89 (1H,d), 4.96 (m,1H), 4.63 (m, 1H), 4.28 (m,1H), 2.10-2.25 (m, 2H), 1.44-1.65 (m, 3H),1.17-1.20 (m, 3H), 0.93-0.97 (m, 9H); Liquid/Chromatgraphy/Electrospraymass spec: M+H⁺=593.23

Example 23 Preparation of 5-Fluoro-3-methyl-benzofuran-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

Following the procedure of Example 12 (a-m), except substituting“1-oxy-pyridine-2-sulfonyl chloride” for “pyridine-2-sulfonyl chloride”and “5-Fluoro-3-methyl-benzofuran-2-carboxylic acid” for“quinoline-6-carboxylic acid” gave the title compound: 1H NMR: 8.15 (1H,d), 8.03 (1H, d), 7.31-7.39(m, 3H), 7.18 (m, 1H), 7.17 (m, 1H), 7.07 (d,1H), 7.06 (d, 1H), 4.85 (m, 1H), 4.62 (m, 1H), 4.31 (m, 1H), 2.05-2.22(m, 3H), 1.44-1.66 (m, 4H), 0.92-0.99 (m, 12H);Liquid/Chromatgraphy/Electrospray mass spec: M+H⁺=589.21

Example 24 Preparation of 5-Fluoro-benzofuran-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

Following the procedure of Example 12 (a-m), except substituting“1-oxy-pyridine-2-sulfonyl chloride” for “pyridine-2-sulfonyl chloride”and “5-Fluoro-benzofuran-2-carboxylic acid” for “quinoline-6-carboxylicacid” gave the title compound: 1H NMR: 8.22 (1H, d), 8.12 (1H, d),7.32-7.46 (m, 7H), 7.13 (m, 1H), 6.98 (m, 1H), 5.05 (m, 1H), 4.76 (m,1H), 4.36 (m, 1H), 2.11-2.28 (m, 2H), 1.51-1.78 (m, 3H), 0.99-1.02 (m,12H); Liquid/Chromatgraphy/Electrospray mass spec: M+H⁺=575.16

Example 25 Preparation of 3-Methyl-furo[3,2-b]]pyridine-2-carboxylicacid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

Following the procedure of Example 12 (a-m), except substituting“1-oxy-pyridine-2-sulfonyl chloride” for “pyridine-2-sulfonyl chloride”and “3-Methyl-furo[3,2-b]]pyridine-2-carboxylic acid” for“quinoline-6-carboxylic acid” gave the title compound: 1H NMR: 8.56 (1H,d), 8.16 (1H, d), 8.03 (d, 1H), 7.73 (d, 1H), 7.38 (m, 1H), 7.29-7.34(m, 2H), 7.13 (d, 1H), 6.93 (d, 1H), 4.97 (m, 1H), 4.66 (m, 1H), 4.26(m, 1H), 2.05-2.13 (m, 2H), 1.46-1.67 (m, 3H), 1.11-1.16 (m, 3H),0.92-0.97 (m, 9H); Liquid/Chromatgraphy/Electrospray mass spec:M+H⁺=572.23

Example 26 Preparation of Cyclohexanecarboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

Following the procedure of Example 12 (a-m), except substituting“1-oxy-pyridine-2-sulfonyl chloride” for “pyridine-2-sulfonyl chloride”and “Cyclohexanecarboxylic acid” for “quinoline-6-carboxylic acid” gavethe title compound: 1H NMR: 8.23 (d, 1H), 8.11 (dd, 1H), 7.46 (m, 1H),7.39 (t, 1H), 6.90 (m, 1H), 5.91 (m, 1H), 4.98 (m, 1H), 4.87 (d, 1H),4.48 (m, 1H), 4.36 (m, 1H), 3.96 (d, 1H), 2.24-2.08 (m, 2H), 1.90-1.62(m, 10H), 1.54-1.39 (m, 3H), 1.33-1.21 (m, 3H), 1.05 (d, 3H), 0.95 (m,6H); Electrospray mass spec: M+H⁺=523.4.

Example 27 Preparation of(S)-2-(2-Cyclohexyl-ethanoylamino)-4-methyl-pentanoic acid[(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-yl]-amide

Following the procedure of Example 12 (a-m), except substituting“1-oxy-pyridine-2-sulfonyl chloride” for “pyridine-2-sulfonyl chloride”and “Cyclohexyl-acetic acid” for “quinoline-6-carboxylic acid” gave thetitle compound: 1H NMR: 8.23 (d, 1H), 8.11 (dd, 1H), 7.45 (t, 1H), 7.39(t, 1H), 6.95 (m, 1H), 5.95 (m, 1H), 4.99 (m, 1H), 4.87 (d, 1H), 4.48(m, 1H), 4.36 (m, 1H), 3.96 (d, 1H), 2.18 (m, 2H), 2.07 (m, 2H), 1.91(m, 2H), 1.74-1.58 (m, 10H), 1.53 (m, 2H), 1.34-1.12 (m, 3H), 1.05 (d,3H), 0.95 (m, 6H); Electrospray mass spec: M+H⁺=537.4.

Example 28 Preparation of(S)-2-(3-Cyclohexyl-propanoylamino)-4-methyl-pentanoic acid[(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-yl]-amide

Following the procedure of Example 12 (a-m), except substituting“1-oxy-pyridine-2-sulfonyl chloride” for “pyridine-2-sulfonyl chloride”and “3-cyclohexyl-propionic acid” for “quinoline-6-carboxylic acid” gavethe title compound: 1H NMR: 8.23 (d, 1H), 8.11 (dd, 1H), 7.45 (m, 1H),7.39 (t, 1H), 6.90 (m, 1H), 5.93 (m, 1H), 4.99 (m, 1H), 4.87 (d, 1H),4.48 (m, 1H), 4.38 (m, 1H), 3.97 (d, 1H), 2.25-2.19 (m, 4H), 1.80 (m,2H), 1.71-1.50 (m, 12H), 1.28-1.15 (m, 4H), 1.05 (d, 3H), 0.95 (m, 6H);Electrospray mass spec: M+H⁺=551.4.

Example 29 Preparation of(S)-2-(4-Cyclohexyl-butanoylamino)-4-methyl-pentanoic acid[(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-yl]-amide

Following the procedure of Example 12 (a-m), except substituting“1-oxy-pyridine-2-sulfonyl chloride” for “pyridine-2-sulfonyl chloride”and “4-cyclohexyl-butyric acid” for “quinoline-6-carboxylic acid” gavethe title compound: 1H NMR: 8.22 (d, 1H), 8.11 (dd, 1H), 7.44 (m, 1H),7.39 (t, 1H), 6.86 (d, 1H), 5.87 (d, 1H), 5.00 (m, 1H), 4.87 (d, 1H),4.50 (m, 1H), 4.39 (m, 1H), 3.97 (d, 1H), 2.18 (m, 4H), 1.74-1.50 (m,12H), 1.28-1.12 (m, 6H), 1.05 (d, 3H), 0.95 (m, 6H), 0.91-0.86 (m, 2H);Electrospray mass spec: M+H⁺=565.4.

Example 30 Preparation of(S)-2-(5-Cyclohexyl-pentanoylamino)-4-methyl-pentanoic acid[(4S,7R)-7-methyl-3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-yl]-amide

Following the procedure of Example 12 (a-m), except substituting“1-oxy-pyridine-2-sulfonyl chloride” for “pyridine-2-sulfonyl chloride”and “5-cyclohexyl-pentanoic acid” for “quinoline-6-carboxylic acid” gavethe title compound: 1H NMR: 8.23 (d, 1H), 8.11 (d, 1H), 7.46 (m, 1H),7.39 (t, 1H), 6.88 (d, 1H), 5.88 (m, 1H), 5.01 (m, 1H), 4.88 (d, 1H),4.50 (m, 1H), 4.38 (m, 1H), 3.97 (d, 1H), 2.20 (m, 4H), 1.71-1.50 (m,12H), 1.34 (m, 2H), 1.26-1.13 (m, 6H), 1.05 (d, 3H), 0.95 (m, 6H),0.91-0.85 (m, 2H); Electrospray mass spec: M+H⁺=579.4.

Example 31 Preparation of Benzofuran-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(5-trifluoromethyl-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

Following the procedure of Example 12 (a-m), except substituting“5-trifluoromethyl-pyridine-2-sulfonyl chloride” for“pyridine-2-sulfonyl chloride” and “benzofuran-2-carboxylic acid” for“quinoline-6-carboxylic acid” gave the title compound: 1H NMR: 8.95 (s,1H), 8.10-8.20 (m, 2H), 7.65 (d, 1H), 7.30-7.60 (m, 3H), 7.20-7.30 (m,1H), 7.10 (d, 1H), 6.90 (d, 1H), 5.05-5.15 (m, 1H), 4.70-4.80 (m, 2H),4.30-4.45 (m, 1H), 3.80 (d, 1H), 2.10-2.20 (m, 2H), 1.40-1.80 (m, 5H),0.90-1.10 (m, 9H); Electrospray mass spec: M+H⁺=609.2.

Example 32 Preparation of 5-Fluoro-benzofuran-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(5-trifluoromethyl-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

Following the procedure of Example 12 (a-m), except substituting“5-trifluoromethyl-pyridine-2-sulfonyl chloride” for“pyridine-2-sulfonyl chloride” and “5-fluoro-benzofuran-2-carboxylicacid” for “quinoline-6-carboxylic acid” gave the title compound: 1H NMR:9.0 (s, 1H), 8.20 (d, 1H), 8.12 (d, 1H), 7.40-7.50 (m, 2H), 7.30 (d,1H), 7.20 (d, 1H), 6.90 (d, 1H), 5.05-5.15 (m, 1H), 4.65-5.75 (m, 2H),4.40-4.50 (m, 1H), 3.90 (d, 1H), 2.00-2.30 (m, 2H), 1.50-1.80 (m, 5H),0.95-1.10 (m, 9H); Electrospray mass spec: M+H⁺=627.2.

Example 33 Preparation of Thieno[3,2-b]thiophene-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(5-trifluoromethyl-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

Following the procedure of Example 12 (a-m), except substituting“5-trifluoromethyl-pyridine-2-sulfonyl chloride” for“pyridine-2-sulfonyl chloride” and “thieno[3,2-b]thiophene-2-carboxylicacid” for “quinoline-6-carboxylic acid” gave the title compound: 1H NMR:9.0 (s, 1H), 8.10-8.20 (m, 2H), 7.80 (s, 1H), 7.50 (s, 1H), 7.25 (s,1H), 7.0 (d, 1H), 6.80 (d, 1H), 5.0-5.10 (m, 1H), 4.60-4.80 (m, 2H),4.40-4.50 (m, 1H), 3.90 (d, 1H), 2.10-2.20 (m, 2H), 1.50-1.80 (m, 5H),0.9-1.0 (m, 9H); Electrospray mass spec: M+H⁺=631.2.

Example 34 Preparation of Benzofuran-2-carboxylic acid{1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-cyclohexyl}-amide

Following the procedure of Example 12 (a-m), except substituting“N-Boc-amino-cyclohexane carboxylic acid” for “Boc-L-leucine” and“benzofuran-2-carboxylic acid” for “quinoline-6-carboxylic acid” gavethe title compound: 1H NMR: 8.74-8.73 (s, 1H), 8.02-7.91(m, 2H),7.71-7.69(d, 1H), 7.58-7.28(m, 6H), 6.73(s, 1H) 5.10-5.08(m, 1H),4.78-4.73(d,1H), 4.44-4.13(m, 1H), 3.86-3.81(d, 1H), 2.33-2.01 (m, 6H),1.98-1.40(m,8H), 0.99-0.97(d, 3H); Electrospray mass spec: M+H⁺=553.4.

Example 35 Preparation of Thiophene-3-carboxylic acid{(S)-3,3-dimethyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

Following the procedure of Example 12 (a-m), except substituting“N-Boc-tert-butylalanine” for “Boc-L-leucine” and“thiophene-3-carboxylic acid” for “quinoline-6-carboxylic acid” gave thetitle compound: 1H NMR: 8.72(m, 1H), 7.96(m, 2H), 7.48(m, 2H), 7.00(m,3H), 6.60(m, 2H), 5.18(m, 1H), 4.67(m, 2H), 4.42(m, 1H), 3.88(m, 1H),2.87(m, 2H), 2.22(m, 2H), 1.95(m, 1H), 1.70(m, 2H), 1.01(m, 12H);Electrospray mass spec: M+H⁺=521.4.

Example 36 Preparation of Furan-2-carboxylic acid{(S)-3,3-dimethyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

Following the procedure of Example 12 (a-m), except substituting“N-Boc-tert-butylalanine” for “Boc-L-leucine” and “furan-2-carboxylicacid” for “quinoline-6-carboxylic acid” gave the title compound: 1H NMR:8.73(d, 1H), 7.95(m, 3H), 7.54(m,1H), 7.41(m, 1H), 7.32(m, 1H), 7.26(s,1H), 7.01(d, 1H), 6.56(d, 1H), 5.08(m, 1H), 4.73(m, 2H), 4.43(m, 1H),3.88(d, 1H), 2.18(m, 2H), 1.70(m, 3H), 1.04(s, 9H), 0.98(d, 3H);Electrospray mass spec: M+H⁺⁼505.4.

Example 37 Preparation of Thieno[3,2-b]thiophene-2-carboxylic acid{(S)-3,3-dimethyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide

Following the procedure of Example 12 (a-m), except substituting“N-Boc-tert-butylalanine” for “Boc-L-leucine” and“thieno[3,2-b]thiophene-2-carboxylic acid” for “quinoline-6-carboxylicacid” gave the title compound: 1H NMR: 8.73(d, 1H), 7.92(m, 3H), 7.52(m,2H), 7.27(m, 1H), 7.09(br, 1H), 6.80(br, 1H), 5.10(m,1H), 4.77(m, 2H),4.40(m,1H), 3.87(d,1H), 1.90(m, 5H), 1.05(s, 9H), 0.95(d, 3H);Electrospray mass spec: M+H⁺=577.2.

Example 38 Preparation of Benzofuran-2-carboxylic acid{(S)-2-cyclohexyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide

Following the procedure of Example 12 (a-m), except substituting“N-Boc-L-cyclohexylalanine” for “Boc-L-leucine” and“benzofuran-2-carboxylic acid” for “quinoline-6-carboxylic acid” gavethe title compound: 1H NMR: 8.74(d, 1H), 7.96(m, 3H), 7.55(m, 1H),7.42(m, 2H), 7.28(m, 2H), 6.77(d, 1H), 6.51(m, 1H), 5.14(m, 1H), 4.77(d,1H), 4.69(m, 1H), 4.43(m, 1H), 3.85(d, 1H), 2.18(m, 2H), 1.85-0.98(m,18H); Electrospray mass spec: M+H⁺=581.3.

Example 39 Preparation of Furan-2-carboxylic acid{(S)-2-cyclohexyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide

Following the procedure of Example 12 (a-m), except substituting“N-Boc-L-cyclohexylalanine” for “Boc-L-leucine” and “furan-2-carboxylicacid” for “quinoline-6-carboxylic acid” gave the title compound: 1H NMR:8.73(d, 1H), 7.62(m, 2H), 7.53(m, 2H), 7.13(s, 1H), 6.94(d, 1H), 6.77(d,1H), 6.51(m, 1H), 5.18(m, 1H), 4.77(d, 1H), 4.63(m,1H), 4.25(m, 1H),3.86(d, 1H), 2.10(m, 2H), 1.87-0.93(m, 18H); Electrospray mass spec:M+H⁺=531.2.

Example 40 Preparation of Thiophene-3-carboxylic acid{(S)-2-cyclohexyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide

Following the procedure of Example 12 (a-m), except substituting“N-Boc-L-cyclohexylalanine” for “Boc-L-leucine” and“thiophene-3-carboxylic acid” for “quinoline-6-carboxylic acid” gave thetitle compound: 1H NMR: 8.74(d, 1H), 8.00(m, 2H), 7.66(d,1H), 7.46(m,3H), 7.28(d, 1H), 6.90(d, 1H), 5.14(m, 1H), 4.43(m, 1H), 3.82(d,1H),2.16(m, 2H), 1.90-0.96(m, 18H); Electrospray mass spec: M+H⁺=547.2.

Example 41 Preparation of 3-Methyl-furo[3,2-b]-pyridine-2-carboxylicacid{(S)-2-cyclohexyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide

Following the procedure of Example 12 (a-m), except substituting“N-Boc-L-cyclohexylalanine” for “Boc-L-leucine” and“3-Methyl-furo[3,2-b]-pyridine-2-carboxylic acid” for“quinoline-6-carboxylic acid” gave the title compound: 1H NMR: 8.75(d,1H), 7.98(m, 2H), 7.55(m, 1H), 7.40(m, 2H), 7.33(m, 1H), 6.75(d, 1H),6.50(m, 1H), 5.09(m,1H), 4.79(d, 1H), 4.68(m, 1H), 4.47(m, 1H), 3.87(d,1H), 2.55(s,3H), 2.17(m, 1H), 1.93-0.93(m, 19H); Electrospray mass spec:M+H⁺=596.4.

Example 42 Preparation of(2R,4aR,8aR)-Octahydro-benzo[1,4]dioxine-2-carboxylic acid[(S)-1-((4S,7R)-1-methanesulfonyl-7-methyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide

Following the procedure of Example 12 (a-m), except substituting “methylsulfonylchloride” for “pyridine-2-sulfonyl chloride” and“(2R,4aR,8aR)-Octahydro-benzo[1,4]dioxine-2-carboxylic acid” for“quinoline-6-carboxylic acid” gave the title compound: 1H NMR: 7.65 (d,1H), 5.0 (d, 1H), 4.45-4.50 (m, 1H), 4.30-4.35 (m, 1H), 4.25 (d, 1H),4.0 (d, 1H), 3.80 (d, 1H), 3.50 (t, 1H), 3.30 (s, 2H), 3.15-3.2 (m, 1H),3.30 (s, 1H), 1.3-2.2 (m, 15H), 1.20 (d, 3H), 0.0 (t, 6H); Electrospraymass spec: M+H⁺=502.4.

Example 43 Preparation of Furan-2-carboxylic acid[(S)-2-cyclohexyl-1-((4S,7R)-7-methyl-3-oxo-1-propyl-azepan-4-ylcarbamoyl)-ethyl]-amide

a.[(S)-2-Cyclohexyl-1-((3S,4S,7R)-3-hydroxy-7-methyl-1-propyl-azepan-4-ylcarbamoyl)-ethyl]-carbamicacid tert-butyl ester

[(S)-2-Cyclohexyl-1-((3S,4S,7R)-3-hydroxy-7-methyl-azepan-4-ylcarbamoyl)-ethyl]-carbamicacid-tert-butyl ester (Example 12 a-e, except substituting“Boc-L-cyclohexylalanine” for “Boc-L-leucine”, 1.5 g, 3.78 mmol) wasdissolved in CH₂Cl₂(30 mL), then propionaldehyde (0.41 mL, 5.67 mmol)was added. Then, sodium borohydride (1.6 g, 7.56 mmol) was added and thereaction mixture was stirred at RT for 1 h. The reaction mixture wasconcentrated in vacuo by rotary evaporation, then the filtrate (silicagel, 14% MeOH/CH₂Cl₂) to yield the title compound as a white solid (84%,1.4 g): Electrospray mass spec: M+H⁺=440.4.

b.(S)-2-Amino-3-cyclohexyl-N-((3S,4S,7R)-3-hydroxy-7-methyl-1-propyl-azepan-4-yl)-propionamide

HCl in dioxane (4.0 M, 15 ml) was added to a stirred solution of[(S)-2-Cyclohexyl-1-((3S,4S,7R)-3-hydroxy-7-methyl-1-propyl-azepan-4-ylcarbamoyl)-ethyb.l]-carbamicacid tert-butyl ester (1.4 g, 3.0 mmol) in MeOH (5 ml). The reactionmixture was stirred for 2 h at RT, then was concentrated in vacuo byrotary evaporation and was used in the next reaction without furtherpurification (1.4 g).

c. Furan-2-carboxylic acid[(S)-2-cyclohexyl-1-((3S,4S,7R)-3-hydroxy-7-methyl-1-propyl-azepan-4-ylcarbamoyl)-ethyl]-amide

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (0.10 g, 0.53 mmol) wasadded to a solution of furan-2-carboxylic acid (0.059 g, 0.53 mmol),(S)-2-Amino-3-cyclohexyl-N-((3S,4S,7R)-3-hydroxy-7-methyl-1-propyl-azepan-4-yl)-propionamide(0.15 g, 0.36 mmol), 4-methylmorpholine (0.14 g, 0.16 ml, 1.44 mmol),hydroxybenztriazole (0.071 g, 0.53 mmol) in DMF (2.0 ml) and was stirredat RT overnight. The reaction mixture was then warmed to RT and wasstirred overnight. The reaction mixture was diluted with EtOAc (30 ml),washed with H₂O, brine, dried with magnesium sulfate, filtered,concentrated in vacuo by rotary evaporation, and chromatographed (silicagel, 2.5% MeOH/CH₂Cl₂) to yield the title compound (0.12 g, 76%):Electrospray mass spec: M+H⁺=434.2.

d. Furan-2-carboxylic acid[(S)-2-cyclohexyl-1-((4S,7R)-7-methyl-3-oxo-1-propyl-azepan-4-ylcarbamoyl)-ethyl]-amide

Sulfur trioxide-pyridine complex (0.0.35 g, 2.2 mmol) was added to asolution of Furan-2-carboxylic acid[(S)-2-cyclohexyl-1-((3S,4S,7R)-3-hydroxy-7-methyl-1-propyl-azepan-4-ylcarbamoyl)-ethyl]-amide(0.19 g, 0.44 mmol) in DMSO (4.0 ml) and triethylamine (0.61 ml, 4.4mmol) was stirred at RT for 1 h. The reaction mixture was diluted withwater, then was extracted with EtOAc. Then, the organic layer was wasextracted with brine. The combined organics were dried with magnesiumsulfate, filtered, concentrated in vacuo, and purified by columnchromatography (3% methanol/methylene chloride) gave the title compound(0.15 mg, 79%): 1H NMR: 7.44(s, 1H), 7.11(d, 1H), 7.04(d, 1H), 6.92(d,1H), 6.49(d, 1H), 5.29(m, 1H), 4.69(m, 1H), 3.40(d, 1H), 3.08(m, 2H),2.51(m, 2H), 1.88-0.81(m, 29H); Electrospray mass spec: M+H⁺=432.2.

Example 44 Preparation of Thiophene-3-carboxylic acid[(S)-2-cyclohexyl-1-((4S,7R)-7-methyl-3-oxo-1-propyl-azepan-4-ylcarbamoyl)-ethyl]-amide

Following the procedure of Example 43 (a-d), except substituting“thiophene-3-carboxylic acid” for “furan-2-carboxylic acid” gave thetitle compound: 1H NMR: 7.62(d, 1H), 7.40(d, 1H), 7.04(d, 1H), 6.80(d,1H), 6.45(d,1H), 5.27(m, 1H), 4.66(m,1H), 3.44(d, 1H), 3.09(m, 2H),2.54(m, 2H), 1.87-0.87(m, 29H); Electrospray mass spec: M+H⁺=448.4.

Example 45 Preparation of Benzofuran-2-carboxylic acid[(S)-2-cyclohexyl-1-((4S,7R)-7-methyl-3-oxo-1-propyl-azepan-4-ylcarbamoyl)-ethyl]-amide

Following the procedure of Example 43 (a-d), except substituting“benzofuran-2-carboxylic acid” for “furan-2-carboxylic acid” gave thetitle compound: 1H NMR: 7.98(d, 1H), 7.45(m, 2H), 7.27(s, 2H), 6.90(d,1H), 6.50(d, 1H), 5.28(m,1H), 4.67(m, 1H), 3.40(d, 1H), 3.06(m, 2H),2.56(m, 2H), 1.88-0.80(m, 29H); Electrospray mass spec: M+H⁺=482.4.

Example 46 Preparation of1-(3-Cyclohexyl-propanoylamino)-cyclohexanecarboxylic acid((4S,7R)-1-cyclohexylmethyl-7-methyl-3-oxo-azepan-4-yl)-amide

Following the procedure of Example 43 (a-d), except substituting“N-Boc-amino-cyclohexane carboxylic acid” for “Boc-L-cyclohexylalanine”and “cyclohexanecarbaldehyde” for “propionaldehyde” and“cyclohexyl-3-propionic acid” for “furan-2-carboxylic acid” gave thetitle compound: 1H NMR: 7.40 (d, 1H), 7.15 (d, 1H), 5.10-5.20 (m, 1H),3.40 (d, 1H), 3.00-3.10 (m, 2H), 0.80-2.40 (m, 45H); Electrospray massspec: M+H⁺=502.4.

Example 47 Preparation of Benzofuran-2-carboxylic acid[1-((4S,7R)-1-cyclohexylmethyl-7-methyl-3-oxo-azepan-4-ylcarbamoyl)-cyclohexyl]-amide

Following the procedure of Example 43 (a-d), except substituting“N-Boc-amino-cyclohexane carboxylic acid” for “Boc-L-cyclohexylalanine”and “cyclohexanecarbaldehyde” for “propionaldehyde” and“benzofuran-2-carboxylic acid” for “furan-2-carboxylic acid” gave thetitle compound: 1H NMR: 7.60 (d, 1H), 7.30-7.50 (m, 3H), 7.15-7.25 (m,2H), 6.60 (s, 1H), 5.00-5.10 (m, 1H), 3.35 (d, 1H), 2.90-3.05 (m, 3H),1.05-2.40 (m, 26H), 0.80 (d, 3H); Electrospray mass spec: M+H⁺=508.4.

Example 48 Preparation of Benzofuran-2-carboxylic acid[(S)-3-methyl-1-((4S,7R)-7-methyl-3-oxo-1-propyl-azepan-4-ylcarbamoyl)-butyl]-amide

Following the procedure of Example 43 (a-d), except substituting“N-Boc-L-leucine” for “Boc-L-cyclohexylalanine” and“benzofuran-2-carboxylic acid” for “furan-2-carboxylic acid” gave thetitle compound: Electrospray mass spec: M+H⁺=442.05 (M+H).

Example 49 Preparation of(2R,5S)-5-((S)-2-tert-Butoxycarbonylamino-4-methyl-pentanoylamino)-2-methyl-6-oxo-azepane-1-carboxylicacid benzyl ester

Following the procedure of Example 12 (m), except substituting“(2R,5S)-5-((S)-2-tert-Butoxycarbonylamino-4-methyl-pentanoylamino)-2-methyl-6-hydroxy-azepane-1-carboxylicacid benzyl ester” for “quinoline-6-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amidegave the title compound: 1H NMR: 7.40-7.35 (m, 5H), 5.26 (m, 1H), 5.13(dd, 1H), 4.91-4.78 (m, 2H), 4.47 (m, 1H), 4.12 (m, 1H), 3.64 (dd, 1H),2.32 (m, 1H), 2.10 (m, 1H), 1.70-1.52 (m, 5H), 1.45 (s, 9H), 1.12 (d,3H), 0.96 (s, 3H), 0.94 (s, 3H); Electrospray mass spec: M+H⁺=512.2.

Example 50 Preparation of Benzofuran-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-1-(1-morpholin-4-yl-methanoyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}-amide

Following the procedure of Example 12 (a-m), except“morpholine-4-carbonyl chloride” for “pyridine-2-sulfonyl chloride” and“benzofuran-2-carboxylic acid” for “quinoline-6-carboxylic acid” gavethe title compound: 1H NMR: 7.62 (d, 1H), 7.51 (d, 1H), 7.38 (m, 1H),7.22 (m, 1H), 7.11 (d, 1H), 4.69 (m, 1H), 3.87 (m, 1H), 3.51 (m, 2H),3.21 (m, 2H), 3.07 (m, 1H), 2.14 (m, 1H), 1.66-1.85 (m, 3H), 1.26 (m,3H), 1.17 (m, 3H), 0.94 (m, 6H); Liquid/Chromatgraphy/Electrospray massspec: M+H⁺=513.21

Example 51 Preparation of(S)-2-(3-Cyclohexyl-propanoylamino)-4-methyl-pentanoic acid[(4S,7R)-7-methyl-1-(1-morpholin-4-yl-methanoyl)-3-oxo-azepan-4-yl]-amide

Following the procedure of Example 12 (a-m), except“morpholine-4-carbonyl chloride” for “pyridine-2-sulfonyl chloride” and“cyclohexyl-3-propionic acid” for “quinoline-6-carboxylic acid” gave thetitle compound: 1H NMR: 6.94 (d, 1H), 5.85 (d, 1H), 4.59 (m, 1H), 4.40(m, 1H), 3.61 (m, 4H), 3.19 (m, 2H), 3.10 (m, 2H), 2.02-2.28 (m, 4H),1.77 (m, 1H), 1.50-1.69 (m, 6H), 1.32-1.46 (m, 4H), 1.25 (d, 2H),1.01-1.19 (m, 4H), 0.87 (m, 6H); Liquid/Chromatgraphy/Electrospray massspec: M+H⁺=507.27.

Example 52 Preparation of(2R,5S)-5-{(S)-2-[(1-Benzofuran-2-yl-methanoyl)-amino]-4-methyl-pentanoylamino}-2-methyl-6-oxo-azepane-1-carboxylicacid (tetrahydro-pyran-4-yl)-amide

Following the procedure of Example 12 (a-m), except“tetrahydro-pyran-4-amino-carbonyl chloride” for “pyridine-2-sulfonylchloride” and “benzofuran-2-carboxylic acid” for “quinoline-6-carboxylicacid” gave the title compound: 1H NMR: 7.65 (d, 1H), 7.40-7.50 (m, 3H),7.20-7.30 (m, 1H), 7.05 (d, 1H), 6.90 (d, 1H), 5.00 (d, 1H), 4.80-4.90(m, 1H), 4.65-4.80 (m, 1H), 4.50 (d, 1H), 3.85-4.00 (m, 4H), 3.40-3.50(m, 5H), 2.30-2.40 (m, 1H), 1.90-2.05 (m, 3H), 1.40-1.75 (m, 5H), 1.20(d, 3H), 1.00 (d, 6H); Electrospray mass spec: M+H⁺=527.4.

Example 53 Preparation of(S)-2-{[1-((2R,5S)-5-{(S)-2-[(1-Benzofuran-2-yl-methanoyl)-amino]-4-methyl-pentanoylamino}-2-methyl-6-oxo-azepan-1-yl)-methanoyl]-amino}-4-methyl-pentanoicacid methyl ester

a.(S)-2-({1-[(2R,5S)-5-((S)-2-tert-Butoxycarbonylamino-4-methyl-pentanoylamino)-2-methyl-6-hydroxy-azepan-1-yl]-methanoyl}-amino)-4-methyl-pentanoicacid methyl ester

[(S)-3-Methyl-1-((4S,7R)-7-methyl-3-hydroxy-azepan-4-ylcarbamoyl)-butyl]-carbamicacid tert-butyl ester (Example 12a-i, 500 mg, 1.4 mmol) was dissolved inTHF (7 ml), then (S)-(−)-2-isocyanato-4-methylvaleric acid methyl ester(180 mg, 1.05 mmol) was added and the reaction mixture was stirred at RTfor 2 h. The reaction mixture was concentrated in vacuo by rotaryevaporation, and chromatographed (silica gel, 1% to 2% MeOH/CH₂Cl₂) toyield the title compound as a white solid (91%, 506 mg): LC/Electrospraymass spec: M+H⁺=529.4.

b.(S)-2-({1-[(2R,S)-5-((S)-2-Amino-4-methyl-pentanoylamino)-2-methyl-6-hydroxy-azepan-1-yl]-methanoyl}-amino)-4-methyl-pentanoicacid methyl ester

4.0 M HCl in dioxane (8 ml) was added to a stirred solution(S)-2-({1-[(2R,5S)-5-((S)-2-tert-Butoxycarbonylamino-4-methyl-pentanoylamino)-2-methyl-6-hydroxy-azepan-1-yl]-methanoyl}-amino)-4-methyl-pentanoicacid methyl ester (490 mg, 0.93 mmol) in MeOH (8 ml). The reactionmixture was stirred for 2.5 h at RT, then was concentrated in vacuo byrotary evaporation and was used in the next reaction without furtherpurification (430 mg).

c.(S)-2-{[1-((2R,5S,6S)-5-{(S)-2-[(1-Benzofuran-2-yl-methanoyl)-amino]-4-methyl-pentanoylamino}-6-hydroxy-2-methyl-azepan-1-yl)-methanoyl]-amino}-4-methyl-pentanoicacid methyl ester

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (214 g, 1.12 mmol) wasadded to a solution of benzofuran-2-carboxylic acid (166 g, 1.02 mmol),(S)-2-({1-[(2R,5S)-5-((S)-2-Amino-4-methyl-pentanoylamino)-2-methyl-6-hydroxy-azepan-1-yl]-methanoyl}-amino)-4-methyl-pentanoicacid methyl ester (430 mg, 0.93 mmol), diisopropylethylamine (240 mg,0.32 ml, 1.86 mmol), hydroxybenztriazole (151 mg, 1.12 mmol) in DMF (5ml) and was stirred at RT overnight. The reaction mixture was stirredovernight. The reaction mixture was diluted with EtOAc (30 ml), washedwith cold aq. 1N HCl, aq. sat. NaHCO₃, and brine, and then dried withmagnesium sulfate, filtered, concentrated in vacuo by rotaryevaporation, and chromatographed (silica gel, 2% to 3% MeOH/CH₂Cl₂) toyield the title compound (478 mg, 84% for two steps): electrospray MS:572.4

d.(S)-2-{[1-((2R,5S,6S)-5-{(S)-2-[(1-Benzofuran-2-yl-methanoyl)-amino]-4-methyl--6-oxo-2-methyl-azepan-1-yl)-methanoyl]-amino}-4-methyl-pentanoic acidmethyl ester

Dess-Martin periodinane (500 mg, 1.18 mmol) was added to a solution of(S)-2-{[1-((2R,5S,6S)-5-{(S)-2-[(1-Benzofuran-2-yl-methanoyl)-amino]-4-methyl-pentanoylamino}-6-hydroxy-2-methyl-azepan-1-yl)-methanoyl]-amino}-4-methyl-pentanoicacid methyl ester (450 mg, 0.79 mmol) in CH₂Cl₂ (16 ml) and was stirredat RT for 3 h. The solution was washed with 10% aq. Na₂S₂O₃, aq. sat.NaHCO₃, and brine. Purification by column chromatography (silica gel, 1%to 2% MeOH/CH₂Cl₂) gave the title compound (405 mg, 90%): 1H NMR (400MHz, CDCl3): δ 7.69 (d, 1H), 7.54 (d, 1H), 7.49 (s, 1H), 7.44 (t, 1H),7.31(t, 1H), 7.08 (d, 1H), 6.91 (d, 1H), 5.03-4.95 (m, 2H), 4.84 (q,1H), 4.71-4.62 (m, 1H), 4.57 (q, 1H), 4.10-4.02 (m, 1H), 3.77 (s, 3H),3.57 (d, 1H), 2.46-2.36 (m, 1H), 2.07-1.99(m, 1H), 1.82-1.41 (m, 8H),1.25 (d, 3H), 1.02 (d, 12H); Electrospray mass spec: M+H⁺=571.4.

Example 54 Preparation of(S)-2-{[1-((2R,5S)-5-{(S)-2-[(1-Benzofuran-2-yl-methanoyl)-amino]-4-methyl-pentanoylamino}-2-methyl-6-oxo-azepan-1-yl)-methanoyl]-amino}-4-methyl-pentanoicacid

a.(S)-2-{[1-((2R,5S,6S)-5-((S)-2-[(1-Benzofuran-2-yl-methanoyl)-amino]-4-methyl-pentanoylamino}-6-oxo-2-methyl-azepan-1-yl)-methanoyl]-amino}-4-methyl-pentanoicacid methyl ester (58 mg, 0.1 mmol) was dissolved in MeOH (1.0 ml) andH₂O (0.5 ml), then potassium carbonate (28 mg, 0.2 mmol) was added andthe reaction mixture was stirred at RT for 20 h. The reaction mixturewas acidified with cold aq. 1N HCl, extracted with CH₂Cl₂, washed withbrine, and then dried with magnesium sulfate. Following filtration,concentration by rotary evaporation, and purification by columnchromatography (silica gel, 2% MeOH/CH₂Cl₂ to 5% MeOH/CH₂Cl₂), the titlecompound (28 mg, 50%) was obtained as a white solid: 1H NMR (400 MHz,DMSO-d₆): δ 8.65 (d, 1H), 8.11 (d, 1H), 7.79 (d, 1H), 7.69 (d, 1H),7.63(s, 1H), 7.48 (t, 1H), 7.35 (t, 1H), 6.60 (br s, 1H), 4.67-4.48 (m,3H), 4.24 (m, 1H), 4.11 (m, 1H), 3.62-3.49 (m, 2H), 2.01-1.09 (m, 10H),1.09 (d, 3H), 0.93-0.81 (m, 12H); Electrospray mass spec: M+H⁺=557.4.

Example 55 Preparation of(S)-2-{[1-(4-{(S)-2-[(1-Benzofuran-2-yl-methanoyl)-amino]-4-methyl-pentanoylamino}-3-oxo-azepan-1-yl)-methanoyl]-amino}-4-methyl-pentanoicacidmethyl ester

Following the procedure of Example 53 (a-d), except substituting“(3S,4S)-4-Amino-3-hydroxy-azepane-1-carboxylic acid benzyl ester(Marquis, R. J. Med. Chem., 2001)” for“(2R,5S,6S)-5-Amino-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzylester” the title compound was obtained: 1H NMR (400 MHz, CDCl₃): δ7.69(d, 1H), 7.54 (d, 1H), 7.49 (s, 1H), 7.44 (t, 1H), 7.31 (t, 1H), 7.08(d, 1H), 6.96 (d, 1H), 5.06-4.97 (m, 2H), 4.77-4.64 (m, 1H), 4.55 (m,1H), 3.93 (d, 1H), 3.77 (s, 3H), 3.61 (d, 1H), 2.93 (t, 1H), 2.28 (m,1H), 2.09 (m, 1H), 1.88 (m, 1H), 1.81-1.24 (m, 7H), 1.01 (d, 12H);Electrospray mass spec: M+H⁺=557.4.

Example 56 Preparation of(S)-2-([1-(4-{(S)-2-[(1-Benzofuran-2-yl-methanoyl)-amino]-4-methyl-pentanoylamino}-3-oxo-azepan-1-yl)-methanoyl]-amino}-4-methyl-pentanoicacid

Following the procedure of Example 54 (a), except substituting“(S)-2-{[1-(4-{(S)-2-[(1-Benzofuran-2-yl-methanoyl)-amino]-4-methyl-pentanoylamino}-3-oxo-azepan-1-yl)-methanoyl]-amino}-4-methyl-pentanoicacid methyl ester” for(S)-2-{[1-((2R,5S,6S)-5-{(S)-2-[(1-Benzofuran-2-yl-methanoyl)-amino]-4-methyl-pentanoylamino}-6-oxo-2-methyl-azepan-1-yl)-methanoyl]-amino}-4-methyl-pentanoicacid methyl ester” the title compound was obtained: 1H NMR (400 MHz,CDCl₃): δ7.69 (d, 1H), 7.58-7.37 (m, 3H), 7.32 (t, 1H), 7.06 (br s, 1H),5.00 (br s, 1H), 4.79-4.63 (m, 2H), 4.58-4.46 (m, 1H), 4.35-4.22 (m,1H), 3.61-3.22 (m, 2H), 2.21-0.69 (m, 24H); Electrospray mass spec:M+H⁺=543.4.

Example 57 Preparation of(S)-4-Methyl-2-{[1-((2R,5S)-2-methyl-5-{(S)-4-methyl-2-[(1-quinolin-8-yl-methanoyl)-amino]-pentanoylamino}-6-oxo-azepan-1-yl)-methanoyl]-amino}-pentanoicacid methyl ester

Following the procedure of Example 53 (a-d), except substituting“Quinoline-8-carboxylic acid” for “Benzofuran-2-carboxylic acid” thetitle compound was obtained: 1H NMR (400 MHz, CDCl₃): δ11.70 (d, 1H),8.98 (d, 1H), 8.87 (d, 1H), 8.32 (d, 1H), 8.01 (d, 1H), 7.71 (t, 1H),7.53 (dd, 1H), 7.34 (d, 1H), 5.05-4.74 (m, 4H), 4.61-4.52 (m, 1H),4.12-4.01 (m, 1H), 3.76 (s, 3H), 3.54 (d, 1H), 2.50-2.33 (m, 1H),2.09-1.97 (m, 1H), 1.93-1.39 (m, 8H), 1.22 (d, 3H), 1.05-0.92 (m, 12H);Electrospray mass spec: M+H⁺=582.4.

Example 58 Preparation of(S)-4-Methyl-2-{[1-((2R,5S)-2-methyl-5-{(S)-4-methyl-2-[(1-quinolin-8-yl-methanoyl)-amino]-pentanoylamino}-6-oxo-azepan-1-yl)-methanoyl]-amino}-pentanoicacid

Following the procedure of Example 54 (a), except substituting“(S)-4-Methyl-2-{[1-((2R,5S)-2-methyl-5-{(S)-4-methyl-2-[(1-quinolin-8-yl-methanoyl)-amino]-pentanoylamino}-6-oxo-azepan-1-yl)-methanoyl]-amino}-pentanoicacid methyl ester” for(S)-2-{[1-((2R,5S,6S)-5-{(S)-2-[(1-Benzofuran-2-yl-methanoyl)-amino]-4-methyl-pentanoylamino}-6-oxo-2-methyl-azepan-1-yl)-methanoyl]-amino}-4-methyl-pentanoicacid methyl ester” the title compound was obtained: 1H NMR (400 MHz,CDCl₃): δ11.78 (d, 1H), 8.93 (d, 1H), 8.86 (d, 1H), 8.32 (d, 1H), 8.01(d, 1H), 7.70 (t, 1H), 7.53 (dd, 1H), 7.29 (d, 1H), 4.94-4.12 (m, 5H),3.96-3.48 (m, 2H), 2.48-0.78 (m, 25H); Electrospray mass spec:M+H⁺=568.2.

Example 59 Preparation of(R)-2-{[1-(4-((S)-2-[(1-Benzofuran-2-yl-methanoyl)-amino]-4-methyl-pentanoylamino}-3-oxo-azepan-1-yl)-methanoyl]-amino}-4-methyl-pentanoicacid methyl ester

Following the procedure of Example 53 (a-d), except substituting“(3S,4S)-4-Amino-3-hydroxy-azepane-1-carboxylic acid benzyl ester” for“(2R,5S,6S)-5-Amino-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzylester” and “(R)-(+)-2-isocyanato-4-methylvaleric acid methyl ester” for“(S)-(−)-2-isocyanato-4-methylvaleric acid methyl ester” the titlecompound was obtained: 1H NMR of a 1:1 mixture of diastereomers (400MHz, CDCl₃): δ7.69 (d, two 1H), 7.57-7.41 (m, two 3H), 7.37-7.30 (m, two1H), 7.16-7.08 (m, two 1H), 7.00 and 6.93 (two d, two 1H), 5.11-4.89 (m,two 2H), 4.78-4.49 (m, two 3H), 3.97-3.88 (m, two 1H), 3.81-3.75 (two s,two 3H), 3.62 and 3.60 (two d, two 1H), 2.97-2.85 (m, two 1H), 2.33-2.02(m, two 2H), 1.88-1.24 (m, two 8H), 1.01 and 0.99 (two d, two 12H);Electrospray mass spec: M+H⁺=571.4.

Example 60 Preparation of(R)-2-{[1-(4-{(S)-2-[(1-Benzofuran-2-yl-methanoyl)-amino]-4-methyl-pentanoylamino}-3-oxo-azepan-1-yl)-methanoyl]-amino}-4-methyl-pentanoicacid

Following the procedure of Example 54 (a), except substituting(R)-2-{[1-(4-{(S)-2-[(1-Benzofuran-2-yl-methanoyl)-amino]-4-methyl-pentanoylamino}-3-oxo-azepan-1-yl)-methanoyl]-amino}-4-methyl-pentanoicacid methyl ester” for(S)-2-{[1-((2R,5S,6S)-5-{(S)-2-[(1-Benzofuran-2-yl-methanoyl)-amino]-4-methyl-pentanoylamino}-6-oxo-2-methyl-azepan-1-yl)-methanoyl]-amino}-4-methyl-pentanoicacid methyl ester” the title compound was obtained: 1H NMR (400 MHz,CDCl₃): δ7.68 (d, 1H), 7.56-7.27 (m, 4H), 7.15-7.05 (m, 2H), 5.55 (d,1H), 5.06 (d, 1H), 4.84 (m, 1H), 4.70 (m, 1H), 4.53 (m, 1H), 3.97 (d,1H), 3.53 (d, 1H), 2.83 (t, 1H), 2.41-2.26 (m, 1H), 2.22-2.10 (m, 1H),1.83-1.38 (m, 8H), 1.07-0.82 (m, 12H); Electrospray mass spec:M+H⁺=543.4.

Example 61 Preparation of 4,5(R,S)-Benzofuran-2-carboxylic acid{(S)-3-methyl-1-[5-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide

a. 3-Methyl-4-nitro-butyric acid ethyl ester

Ethyl 2-crotonate (10 g, 87 mmol) dissolved in nitromethane (23 mL, 438mmol) was added 1,1,3,3,-tetramethylguanidine (2 g, 17 mmol). Thesolution was stirred at RT for 24 h. Ether was added (500 mL) and theorganic phase was washed with 1N HCl (100 mL) and dried over sodiumsulfate. The solution was filtered, concentrated and product purified ona silica gel column to yield 14 g of the tile compound: ¹H NMR (400 MHz,CDCl₃) δ 4.6 (2H), 4.2 (q, 2H), 2.9 (m, 1H), 2.4 (2H), 1.3 (m, 3H),1.01(d, 3H). MS (ESI) 174.0 (M+H)⁺.

b. 3-Methyl-4-nitro-butyaldehyde

To a solution of 3-methyl-4-nitro-butyric acid ethyl ester of Example61a (1.0 g, 5.71 mmol) in dry toluene at −78° C. was slowly added a coldsolution Dibal-H (4 mL, of a 1.5 M solution) so as to maintain theinternal temperature below −65° C. The reaction was stirred for anadditional 2 h. The reaction was then quenched by slowly adding cold(−78° C.) MeOH. again by keeping the internal temperature below −65° C.The resulting white emulsion was slowly poured into ice-cold 1 N HClwith swirling over 15 minutes and the aqueous mixture was then extractedwith EtOAc (3 times). The combined organic layers were washed withbrine, dried over sodium sulfate and concentrated to give the crudeproduct which was then purified on a silica gel column to give the pureproduct as a pale yellow oil. 0.73 g: ¹H NMR (400 MHz, CDCl₃) δ 9.9 (s,1H), 4.5 (dq, 2H), 2.9 (m, 2H), 2.6 (dq, 1H), 1.1(d, 3H).

c. 2-[Benzyl-(3-methyl-4-nitro-butyl)-amino]-ethanol

To a solution of 3-methyl-4-nitro-butyaldehyde (0.73 g, 5.57 mmol) ofExample 61b in methylene chloride (6.0 ml) was added sodiumtriacetoxyborohydride (1.57 g, 7.4 mmol) and N-Benzyl ethanolamine (0.55g, 3.67 mmol). The reaction was stirred for 16 h whereupon it wasquenched with water, diluted with EtOAc, washed with NaHCO₃ and brine.The organic layer was dried over sodium sulfate, concentrated and useddirectly in the following reaction: ¹H NMR (400 MHz, CDCl₃) δ 7.4 (m,6H), 4.2 (dq, 2H), 3.6 (m, 4H), 2.3-2.8 (m, 4H), 1.5 (dm, 4H), 1.01(d,3H). MS (ESI) 265.3 (M+H)⁺.

d. 3,4,5-(R,S)-1-Benzyl-5-methyl-4-nitro-azepan-3-ol

To a stirring solution of oxalyl chloride (2M in CH₂Cl₂) (3.38 mL) inmethylene chloride at −78 was added DMSO (1.25 mL, 17.6 mmol) slowly.After a 15 min stirring, the alcohol (0.60 g, 2.25 mmol) dissolved inmethylene chloride was added slowly. The reaction was continued for afurther 1 h at −78. Triethylamine (4.7 mL, 33.8 mmol) was added and thereaction mixture bought to RT, quenched with water and the productextracted into methylene chloride. The organic layer was dried oversodium sulfate, filtered and concentrated. To the crude product in THFwas added triethyl amine and the mixture stirred for 16 h to give titlecompound. The crude product was purified on a silica gel column: ¹H NMR(400 MHz, CDCl₃) δ 7.4 (m, 5H), 4.2 (d, 1H), 3.8 (s, 1H), 1.4-3 (m, 4H),1.1 (d, 3H), MS (ESI) 265.24 (M+H)⁺.

e. 3,4,5-(R,S)-4-Amino-1-benzyl-5-methyl-azepan-3-ol

To a 10:1 solution of methanol (56 mL) and 12N HCl (5.60 mL) was slowlyadded Zn dust (0.43 g, 6.47 mmol). The compound of Example 61d (171 mg,0.65 mmol) was added and the reaction was heated to reflux for 18 hwhereupon it was concentrated in vacuo to remove the methanol. Theresidue was diluted with ethyl acetate and water and made basic withsolid KOH. The mixture was washed with brine, dried over sodium sulfate,filtered and concentrated to give 120 mg of the title compound: MS (ESI)235.2 (M+H)⁺.

f.[(S)-1-(1-Benzyl-3-hydroxy-5-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamicacid tert-butyl ester

To a solution of the compound from Example 61e (1.12 g, 4.76 mmol) inmethylene chlorode was added Boc-leucine (1.3 g, 4.76 mmol), EDC (1 g,4.76 mmol) and HOBt (0.13 g, 0.96 mmol). This mixture was stirred atroom temperature for 3 hours whereupon it was diluted with ethyl acetateand washed with an aqueous solution of sodium bicarbonate, the organiclayer was dried over sodium sulfate, filtered and concentrated. Thecrude product was purified on a silica gel column to yield the titlecompound: ¹H NMR (400 MHz, CDCl₃) δ 8.1 (d, 2H), 7.3 (m, 3H), 1.5 (d,9H), 1.1 (m, 3H), MS (ESI) 448.4 (M+H)⁺.

g.[(S)-1-(3-hydroxy-5-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamicacid tert-butyl ester

To a solution of the compound of Example 61f in methanol: EtOAc, 1:3 wasadded 10% Pd/C. This mixture was shaken for 16 h on a Parr Hydrogenationapparatus at 45 psi of hydrogen gas. The reaction mixture was filteredthrough a pad of celite and concentrated to give the title compound: MS(ESI) 358.4 (M+H)⁺.

h.{(S)-1-[3-Hydroxy-5-methyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-carbamicacid tert-butyl ester

To a solution of Example 61g (6 g, 16.8 mmol) in methylene chloride wasadded 2-pyridinesulfonyl chloride (3 g, 16.9 mmol) and triethylamine (3mL, 22.5 mmol). The reaction was allowed to stir at room temperature for16 h whereupon it was washed with NaHCO₃. The organic layer was driedover sodium sulfate, filtered, concentrated and purified on a silica gelcolumn to yield 5.36 g of the title compound: ¹H NMR (400 MHz, CDCl₃),δ: 8.7 (d, 1H), 7.9 (m, 2H), 7.4 (m, 1H), 1.7-4.4 (m, 19H), 1.4 (d, 9H),1.01(d, 6H); MS (ESI) 499.1 (M+H)⁺.

i. (S)-2-Amino-4-methyl-pentanoic acid[3-hydroxy-5-methyl-1-(pyridine-2-sulfonyl)-azepan-4-yl]-amide

To a solution of the compound of Example 61 h (5.36 g, 11.57 mmol) inMeOH (2 mL) was added 4M HCl/dioxane (25 mL) and stirred for 2 h. ExcessHCl was removed in vacuo and the residue was azeotropically dried withtoluene (2×'s) to yield the title compound as the hydrochloride salt5.37 g: MS (ESI) 399.2 (M+H)⁺.

j. 3,4,5 (R,S)-Benzofuran-2-carboxylic acid{(S)-3-methyl-1-[5-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide

To a solution of the compound of Example 61i (0.66 g, 1.26 mmol.) inmethylene chlorode was added 2-benzofuran carboxylic acid (0.24 g, 1.51mmol), EDC (0.29 g, 1.51 mmol), HOBt (0.04 g, 0.29 mmol), Et₃N (1 mL).The reaction was stirred at room temperature for 3 hours whereupon itwas washed with an aqueous solution of sodium bicarbonate. The organiclayer was dried over sodium sulfate, filtered and concentrated. Thecrude product was purified on a silica gel column to yield the titlecompound: ¹H NMR (400 MHz, CDCl₃), δ: 8.7 (d, 1H), 7.1-7.9 (m, 8H),1.74.4 (m, 11H), 0.9-1.5 (m, 13H). MS (ESI) 565.08 (M+Na)⁺.

k. 4,5 (R,S) Benzofuran-2-carboxylic acid{(S)-3-methyl-1-[5-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide

To a solution of the compound of Example 61j (0.15 g, 0.27 mmol) inmethylene chloride was added Dess-Martin reagent (0.17 g, 0.41 mmol).The reaction was stirred at room temperature for 1 hour, diluted withmethylene chloride then washed with sodium thiosulfate, sodiumbicarbonate and brine. The organic layer was washed dried over sodiumsulfate, filtered, concentrated and purified on a silica gel column toprovide (0.1 g) of the title compound as a mixture of fourdiastereomers: ¹H NMR (400 MHz, CDCl₃), δ: 8.7 (d, 1H), 7.1-7.9 (m, 8H),1.74.4 (m, 10H), 0.9-1.5 (m, 13H). MS (ESI) 540.08 (M+H).

This mixture was separated by HPLC to provide the 4 individualdiastereomers as white powders.

Example 62 Preparation of (R)-2-Biphenyl-3-yl-4-methyl-pentanoic acid[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-yl]-amide

a. (2R,5R,6R)-5-Azido-6-hydroxy-2-methyl-azepane-1-carboxylic acidbenzyl ester

Sodium azide (1.8 g, 27.7 mmol) was added to a(1R,4R,7S)-4-Methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acidbenzyl ester (2.4 g, 9.2 mmol, Example 1e) and ammonium chloride (1.48g, 27.7 mmol) in MeOH (16 ml) and H₂O (1.6 ml), then was refluxedovernight. The reaction mixture was concentrated in vacuo by rotaryevaporation, then was diluted with water (5 ml) and extracted with EtOAc(10 ml). The organic layer was then extracted with water, brine, driedwith MgSO₄, filtered, concentrated in vacuo by rotary evaporation, andchromatographed (silica gel, 25% EtOAc/hexanes) to yield the titlecompound (1.76 g, 63%); Liquid chromatgraphy/Electrospray mass spec:M+H⁺=305.2.

b. (2R,5R,6R)-5-Amino-6-hydroxy-2-methyl-azepane-1-carboxylic acidbenzyl ester

Triphenylphosphine (2.13 g, 8.14 mmol) was added to a solution(2R,5R,6R)-5-Azido-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzylester (1.65 g, 5.43 mmol) in THF (200 ml) and H₂O (0.8 ml), then washeated to 45 degrees C. overnight. The reaction mixture was then dilutedwith toluene (100 ml×2) and was azeotroped in vacuo by rotaryevaporation twice. The resulting oil was dissolved in MeOH and HCl inEt₂O and the resulting salt was collected following filtration and wasused in the next reaction without further purification (1.7 g,quantitative).

c.(2R,5R,6R)-5-tert-Butoxycarbonylamino-6-hydroxy-2-methyl-azepane-1-carboxylicacid benzyl ester

Boc anhydride (0.9 g, 4.13 mmol) was added to a solution of(2R,5R,6R)-5-Amino-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzylester (1.0 g, 3.18 mmol), triethylamine (0.38 g, 0.53 ml, 3.82 mmol) inTHF (5 ml) and H₂O (5 ml) and was stirred at RT for 1H. The THF andexcess triethylamine were removed in vacuo, then the reaction mixturewas diluted with H₂O (10 ml), extracted with EtOAc (3×20 ml), then thecombined organics were extracted with H₂O (30 ml), brine (30 ml), driedwith MgSO4, filtered through silica gel, concentrated, then used in thenext reaction without further purification (1.0 g, 83%): Electrospraymass spec: M+H⁺=379.2.

d. ((3R,4R,7R)-3-Hydroxy-7-methyl-azepan-4-yl)-carbamic acid tert-butylester

(2R,5R,6R)-5-tert-Butoxycarbonylamino-6-hydroxy-2-methyl-azepane-1-carboxylicacid benzyl ester (0.9 g, 2.4 mmol) was dissolved in EtOAc (40 ml), then10% Pd/C (0.45 g) was added and the reaction mixture was degasses bybubbling argon for 5 minutes. Then, the reaction was stirred overnightunder a balloon filled with hydrogen gas. The reaction mixture wasfiltered through Celite, concentrated in vacuo by rotary evaporation andwas azeotroped with toluene (20 ml), then was used in the next reactionwithout further purification (0.58 g, quantitative): Electrospray massspec: M+H⁺=245.2.

e.[(3R,4R,7R)-3-Hydroxy-7-methyl-1-(pyridine-2-sulfonyl)-azepan-4-yl]-carbamicacid tert-butyl ester

Pyridine-2-sulfonyl chloride (0.55 g, 3.1 mmol) was added to a solution((3R,4R,7R)-3-Hydroxy-7-methyl-azepan-4-yl)-carbamic acid tert-butylester (0.58 g, 0.2.4 mmol), sodium bicarbonate (0.84 g, 10 mmol) inCH₂Cl₂ (10 ml) and H₂O (3 ml) and was stirred at RT for 30 minutes. Thereaction mixture was diluted with EtOAc (100 ml), washed with H₂O,brine, dried with magnesium sulfate, filtered, concentrated in vacuo byrotary evaporation, and chromatographed (silica gel, 45:55EtOAC/hexanes) to yield the title compound (0.6 g, 65%): Electrospraymass spec: M+H⁺=386.27.

f. (3R,4R,7R)-4-Amino-7-methyl-1-(pyridine-2-sulfonyl)-azepan-3-ol

HCl in dioxane (4.0 M, 10 ml) was added to a stirred solution.[(3R,4R,7R)-3-Hydroxy-7-methyl-1-(pyridine-2-sulfonyl)-azepan-4-yl]-carbamicacid tert-butyl ester (0.6 g, 1.55 mmol) in MeOH (10 ml). The reactionmixture was stirred for 1 h at RT, then was diluted with toluene (20ml), concentrated in vacuo by rotary evaporation and was used in thenext reaction without further purification (0.5 g, quantitative):Electrospray mass spec: M+H⁺=286.2.

g. 2-Biphenyl-3-yl-4-methyl-pentanoic acid[(3R,4R,7R)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-yl]-amide

2-Biphenyl-3-yl-4-methyl-pentanoic acid (270 mg, 1.0 mmol, preparationdescribed in J. Am. Chem. Soc. 1997, 120, 9114), and(3R,4R,7R)-4-Amino-7-methyl-1-(pyridine-2-sulfonyl)-azepan-3-ol (320 mg,1.0 mmol, Example 1k), EDCI (190 mg, 1.0 mmol), HOBT (135 mg, 1.0 mmol)and diisopropylethylamine (1.7 g, 0.23 ml, 1.3 mmol) in DMF (5 ml) werestirred at RT for 4 h. The reaction mixture was diluted with EtOAc (20ml), washed with H₂O, brine, dried with magnesium sulfate, filtered,concentrated in vacuo by rotary evaporation, and chromatographed (silicagel, 40% EtOAc/hexanes) to yield the title compound (330 mg, 62%): ¹HNMR (400 MHz, CDCl₃): δ 8.55-8.60 (m, 1H), 8.00 (t, 1H), 7.80-7.90 (m,1H), 7.65 (d, 2H), 7.25-7.55 (m, 8H), 5.50-5.60 (m, 1H), 4.00-4.10 (m,1H), 3.70-3.85 (m, 1H), 3.50-3.70 (m, 2H), 2.90-3.05 (m, 1H), 2.00-2.10(m, 2H), 1.30-1.85 (m, 5H), 0.90-0.95 (d, 9H); ESMS: 536.4 (M+H⁺)

h. (R)-2-Biphenyl-3-yl-4-methyl-pentanoic acid[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-yl]-amide

Dess-Martin periodinane (400 mg, 0.93 mmol) was added to a solution2-Biphenyl-3-yl-4-methyl-pentanoic acid[(3R,4R,7R)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-yl]-amide(330 mg, 0.62 mmol) in CH₂Cl₂ (15 ml) and was stirred at RT for 4 h. Thesolution was washed with 10% aq. Na₂S₂O₃, aq. sat. NaHCO₃, and brine,then concentrated in vacuo, then chromatographed (silica gel, 50%EtOAc/hexanes) to provide a mixture of diasteromers (260 mg, 60%), whichwas then dissolved in MeOH (12 ml) and triethylamine (0.44 g, 0.6 ml,4.4 mmol), and was stirred at RT for 3 days. The reaction mixture wasconcentrated in vacuo, then chromatographed to yield a mixure ofprimarily (R)- and (S)-2-Biphenyl-3-yl-4-methyl-pentanoic acid[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-yl]-amides (200mg, 77%). The diastereomers were separated using HPLC (R,R-Whelk-Opreparative column, 40% EtOH/hexanes): Diastereomer 1 (retention time 13min): ¹H NMR (400 MHz, CDCl₃): δ 8.70 (d, 1H), 8.00 (d, 1H), 7.90 (t,1H), 7.60 (d, 2H), 7.25-7.55 (m, 8H), 6.52 (d, 1H), 5.05-5.15 (m, 1H),4.75 (d, 1H), 4.35-4.45 (m, 1H), 3.82 (d, 1H), 3.50 (t, 1H), 2.00-2.20(m, 3H), 1.70-1.80 (m, 1H), 1.40-1.65 (m, 2H), 1.25-1.40 (m, 1H),0.9-1.0 (m, 9H); ESMS: 534.2 (M+H⁺);

Diastereomer 2 (retention time 21 min): ¹H NMR (400 MHz, CDCl₃): δ 8.65(d, 1H), 8.00 (d, 1H), 7.90 (t, 1H), 7.60 (d, 2H), 7.25-7.60 (m, 8H),6.60 (d, 1H), 4.95-5.02 (m, 1H), 4.70 (d, 1H), 4.40-4.50 (m, 1H), 3.85(d, 1H), 3.50 (t, 1H), 2.12-2.30 (m, 2H), 2.00-2.10 (m, 1H), 1.70-1.80(m, 1H), 1.60-1.70 (m, 1H), 1.40-1.60 (m, 2H), 1.00 (d, 3H), 0.95 (d,6H); ESMS: 534.2 (M+H⁺)

Example 63 Preparation of 3-Methyl-furo[3,2-b]-pyridine-2-carboxylicacid{1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-cyclohexyl}-amide

Following the procedure of Example 12 (a-m), except substituting“N-Boc-amino-cyclohexane carboxylic acid” for “Boc-L-leucine” and“3-Methyl-furo[3,2-b]-pyridine-2-carboxylic acid” for“quinoline-6-carboxylic acid” gave the title compound: 1H NMR: 8.72(d,1H), 8.65(d, 1H), 7.98(m, 1H), 7.90(m, 1H), 7.80(d, 1H), 5.11(m, 1H),4.76(d, 1H), 4.43(m, 1H), 3.81(d, 1H), 2.82(s, 3H), 2.32-1.35(m, 14H),0.95(d, 3H);

Electrospray mass spec: M+H⁺=568.2.

Example 64 Preparation of1-(3-Cyclohexyl-propanoylamino)-cyclohexanecarboxylic acid[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-yl]-amide

Following the procedure of Example 12 (a-m), except substituting“N-Boc-amino-cyclohexane carboxylic acid” for “Boc-L-leucine” and“3-Cyclohexyl-propananoic acid” for “quinoline-6-carboxylic acid” gavethe title compound: 1H NMR: 8.71(d, 1H), 7.97(m, 2H), 7.72(m, 3H),6.60(s, 1H), 5.04(m, 1H), 4.71(d, 1H), 4.42(m, 1H), 3.81(d, 1H),2.27-0.73(m, 31H); Electrospray mass spec: M+specification and Examplesfully disclose how to make and use the compounds of the presentinvention H⁺=544.4.

The above specification and Examples fully disclose how to make and usethe compounds of the present invention. However, the present inventionis not limited to the particular embodiments described hereinabove, butincludes all modifications thereof within the scope of the followingclaims. The various references to journals, patents and otherpublications which are cited herein comprise the state of the art andare incorporated herein by reference as though fully set forth.

1. A compound which is 3-methyl-furo[3,2-b]pyridine-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;or a pharmaceutically acceptable salt thereof.
 2. A pharmaceuticalcomposition comprising a compound according to claim 1 and apharmaceutically acceptable carrier, diluent or excipient.
 3. A methodof treating osteoporosis by administering to a patient in need thereofan effective amount of a compound according to claim
 1. 4. A method oftreating periodontitis by administering to a patient in need thereof aneffective amount of a compound according to claim
 1. 5. A method oftreating gingivitis by administering to a patient in need thereof aneffective amount of a compound according to claim
 1. 6. A method oftreating osteoarthritis by administering to a patient in need thereof aneffective amount of a compound according to claim
 1. 7. A method oftreating rheumatoid arthritis by administering to a patient in needthereof an effective amount of a compound according to claim 1.